THIAZOLES AS MODULATORS OF RORyt

ABSTRACT

The present invention comprises compounds of Formula I. 
     
       
         
         
             
             
         
       
     
     wherein:
 
R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and
 
     
       
         
         
             
             
         
       
     
     are defined in the specification. 
     The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim  1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Application No. 62/072,614,filed on Oct. 30, 2014, which is incorporated herein by reference.

FIELD OF THE INVENTION

The invention is directed to substituted thiazole compounds, which aremodulators of the nuclear receptor RORγt, pharmaceutical compositions,and methods for use thereof. More particularly, the RORγt modulators areuseful for preventing, treating or ameliorating an RORγt mediatedinflammatory syndrome, disorder or disease.

BACKGROUND OF THE INVENTION

Retinoic acid-related nuclear receptor gamma t (RORγt) is a nuclearreceptor, exclusively expressed in cells of the immune system, and a keytranscription factor driving Th17 cell differentiation. Th17 cells are asubset of CD4⁺ T cells, expressing CCR6 on their surface to mediatetheir migration to sites of inflammation, and dependent on IL-23stimulation, through the IL-23 receptor, for their maintenance andexpansion. Th17 cells produce several proinflammatory cytokinesincluding IL-17A, IL-17F, IL-21, and IL-22 (Korn, T., E. Bettelli, etal. (2009). “IL-17 and Th17 Cells.” Annu Rev Immunol 27: 485-517), whichstimulate tissue cells to produce a panel of inflammatory chemokines,cytokines and metalloproteases, and promote recruitment of granulocytes(Kolls, J. K. and A. Linden (2004). “Interleukin-17 family members andinflammation.” Immunity 21(4): 467-76; Stamp, L. K., M. J. James, et al.(2004). “Interleukin-17: the missing link between T-cell accumulationand effector cell actions in rheumatoid arthritis” Immunol Cell Biol82(1): 1-9). Th17 cells have been shown to be the major pathogenicpopulation in several models of autoimmune inflammation, includingcollagen-induced arthritis (CIA) and experimental autoimmuneencephalomyelitis (EAE) (Dong, C. (2006). “Diversification ofT-helper-cell lineages: finding the family root of IL-17-producingcells.” Nat Rev Immunol 6(4): 329-33; McKenzie, B. S., R. A. Kastelein,et al. (2006). “Understanding the IL-23-IL-17 immune pathway.” TrendsImmunol 27(1): 17-23). RORγt-deficient mice are healthy and reproducenormally, but have shown impaired Th17 cell differentiation in vitro, asignificantly reduced Th17 cell population in vivo, and decreasedsusceptibility to EAE (Ivanov, II, B. S. McKenzie, et al. (2006). “Theorphan nuclear receptor RORgammat directs the differentiation program ofproinflammatory IL-17+ T helper cells.” Cell 126(6): 1121-33). Micedeficient for IL-23, a cytokine required for Th17 cell survival, fail toproduce Th17 cells and are resistant to EAE, CIA, and inflammatory boweldisease (IBD) (Cua, D. J., J. Sherlock, et al. (2003). “Interleukin-23rather than interleukin-12 is the critical cytokine for autoimmuneinflammation of the brain.” Nature 421(6924): 744-8; Langrish, C. L., Y.Chen, et al. (2005). “IL-23 drives a pathogenic T cell population thatinduces autoimmune inflammation.” J Exp Med 201(2): 233-40; Yen, D., J.Cheung, et al. (2006). “IL-23 is essential for T cell-mediated colitisand promotes inflammation via IL-17 and IL-6.” J Clin Invest 116(5):1310-6). Consistent with these findings, an anti-IL23-specificmonoclonal antibody blocks development of psoriasis-like inflammation ina murine disease model (Tonel, G., C. Conrad, et al. “Cutting edge: Acritical functional role for IL-23 in psoriasis.” J Immunol 185(10):5688-91).

In humans, a number of observations support the role of the IL-23/Th17pathway in the pathogenesis of inflammatory diseases. IL-17, the keycytokine produced by Th17 cells, is expressed at elevated levels in avariety of allergic and autoimmune diseases (Barczyk, A., W. Pierzchala,et al. (2003). “Interleukin-17 in sputum correlates with airwayhyperresponsiveness to methacholine.” Respir Med 97(6): 726-33; Fujino,S., A. Andoh, et al. (2003). “Increased expression of interleukin 17 ininflammatory bowel disease.” Gut 52(1): 65-70; Lock, C., G. Hermans, etal. (2002). “Gene-microarray analysis of multiple sclerosis lesionsyields new targets validated in autoimmune encephalomyelitis.” Nat Med8(5): 500-8; Krueger, J. G., S. Fretzin, et al. “IL-17A is essential forcell activation and inflammatory gene circuits in subjects withpsoriasis.” J Allergy Clin Immunol 130(1): 145-154 e9). Furthermore,human genetic studies have shown association of polymorphisms in thegenes for Th17 cell-surface receptors, IL-23R and CCR6, withsusceptibility to IBD, multiple sclerosis (MS), rheumatoid arthritis(RA) and psoriasis (Gazouli, M., I. Pachoula, et al. “NOD2/CARD15,ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn'sdisease.” World J Gastroenterol 16(14): 1753-8., Nunez, C., B. Dema, etal. (2008). “IL23R: a susceptibility locus for celiac disease andmultiple sclerosis?” Genes Immun 9(4): 289-93; Bowes, J. and A. Barton“The genetics of psoriatic arthritis: lessons from genome-wideassociation studies.” Discov Med 10(52): 177-83; Kochi, Y., Y. Okada, etal. “A regulatory variant in CCR6 is associated with rheumatoidarthritis susceptibility.” Nat Genet 42(6): 515-9).

Ustekinumab (Stelara®), an anti-p40 monoclonal antibody blocking bothIL-12 and IL-23, is approved for the treatment of adult patients (18years or older), with moderate to severe plaque psoriasis, who arecandidates for phototherapy or systemic therapy. Currently, monoclonalantibodies specifically targeting only IL-23, to more selectivelyinhibit the Th17 subset, are also in clinical development for psoriasis(Garber K. (2011). “Psoriasis: from bed to bench and back” Nat Biotech29, 563-566), further implicating the important role of the IL-23- andRORγt-driven Th17 pathway in this disease. Results from recent phase IIclinical studies strongly support this hypothesis, as anti-IL-17receptor and anti-IL-17 therapeutic antibodies both demonstrated highlevels of efficacy in patients with chronic psoriasis (Papp, K. A.,“Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.” NEngl J Med 2012 366(13): 1181-9; Leonardi, C., R. Matheson, et al.“Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaquepsoriasis.” N Engl J Med 366(13): 1190-9). Anti-IL-17 antibodies havealso demonstrated clinically relevant responses in early trials in RAand uveitis (Hueber, W., Patel, D. D., Dryja, T., Wright, A. M.,Koroleva, I., Bruin, G., Antoni, C., Draelos, Z., Gold, M. H., Durez,P., Tak, P. P., Gomez-Reino, J. J., Foster, C. S., Kim, R. Y., Samson,C. M., Falk, N. S., Chu, D. S., Callanan, D., Nguyen, Q. D., Rose, K.,Haider, A., Di Padova, F. (2010) Effects of AIN457, a fully humanantibody to interleukin-17A, on psoriasis, rheumatoid arthritis, anduveitis. Sci Transl Med 2, 5272).

All the above evidence supports inhibition of the Th17 pathway bymodulating RORγt activity as an effective strategy for the treatment ofimmune-mediated inflammatory diseases.

SUMMARY OF THE INVENTION

The present invention comprises compounds of Formula I:

wherein

is phenyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazyl;

R¹ is H, Cl, OCF₃, C₍₁₋₄₎alkyl, —CN, F, OC₍₁₋₄₎alkyl, OCHF₂, Br, I, orcyclopropyl; wherein said C₍₁₋₄₎alkyl is optionally substituted with upto six fluorine atoms;

R² is H, F, Cl, —CN, OC₍₁₋₄₎alkyl, OCHF₂, OCF₃, cyclopropyl, orC₍₁₋₄₎alkyl; wherein said C₍₁₋₄)alkyl is optionally substituted with upto five fluorine atoms, and said cyclopropyl is optionally substitutedwith OH, CH₃, CF₃, —CN, and up to five fluorine atoms; or R¹ and R² maybe taken together with their attached ring A to form a fused ring systemselected from the group consisting of naphthalenyl, isoquinolinyl,tetrahydronaphthalenyl, quinolinyl, 2,3-dihydro-1H-indenyl, chromanyl,isochromanyl, and naphthyridinyl; wherein said naphthalenyl,isoquinolinyl, tetrahydronaphthalenyl, quinolinyl,2,3-dihydro-1H-indenyl, chromanyl, isochromanyl, and naphthyridinyl areoptionally substituted up to three times with F, C₍₁₋₃₎alkyl, orOC₍₁₋₃₎alkyl; wherein each substituent is selected independently;wherein said OC₍₁₋₃₎alkyl and C₍₁₋₃₎ alkyl is optionally substitutedwith up to five fluorine atoms; provided that R² may not be H if R¹ isH;

R³ is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl,pyridyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, orfuranyl; wherein said oxadiazolyl, thiazolyl, thiadiazolyl,isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, pyridyl,pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, or furanyl isoptionally substituted with R⁶, and further optionally substituted withone substituent selected from the group consisting of F, CH₃, and CF₃;

-   -   R⁶ is

C₍₁₋₆₎alkyl, C(O)NH₂, —CN, C₍₃₋₆₎cycloalkyl, NH₂, NH(C₍₁₋₆₎alkyl),N(C₍₁₋₆₎alkyl)₂, NHCO(C₍₁₋₆₎alkyl), N(C₍₁₋₆₎alkyl)CO(C₍₁₋₆₎alkyl),NHSO₂(C₍₁₋₆₎alkyl), N(C₍₁₋₆₎alkyl)SO₂(C₍₁₋₆₎alkyl), O(C₍₁₋₆₎alkyl),C(O)NH₂, CONH(C₍₁₋₆₎alkyl), CON(C₍₁₋₆₎alkyl)₂, SO₂NH₂,SO₂NH(C₍₁₋₆₎alkyl), SO₂NH(COC₍₁₋₆₎alkyl), or SO₂N(C₍₁₋₆₎alkyl)₂; whereinsaid C₍₁₋₆₎alkyl or C₍₃₋₆₎cycloalkyl is optionally independentlysubstituted with up to six fluorine atoms, CO₂H, OH, —CN, C(O)NH₂, NH₂,OCH₃, OCHF₂, OCF₃, —(CX₂)_(m)—, or N(CH₃)₂;

-   -   wherein m is 2, 3, 4, or 5;    -   X is H, or F; wherein each occurrence of X in a single molecule        is independently defined;

R⁴ is H, C₍₃₋₈₎cycloalkyl, C₍₃₋₈₎alkyl, OC₍₁₋₈₎alkyl, phenyl, pyridyl,CH₂SO₂C₍₁₋₃₎alkyl, NA¹A², CH₂O—C₍₃₋₈₎alkyl, O—C₍₃₋₈₎cycloalkyl,tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, oxadiazolyl,isoxadiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrimidyl,pyridazyl, pyrazyl, imidazolyl, pyrrolyl, or furanyl, wherein saidC₍₃₋₈₎alkyl and O—C₍₃₋₈₎alkyl are optionally substituted with 1 to 4substituents independently selected from F, Cl, OH, OCH₃, OCHF₂, OCF₃,and —CN; and said C₍₃₋₈₎cycloalkyl, O—C₍₃₋₈₎cycloalkyl,tetrahydrofuranyl, tetrahydropyranyl, phenyl, thiadiazolyl, oxadiazolyl,isoxadiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl,pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, and furanyl areoptionally substituted with 1 to 4 substituents independently selectedfrom the group consisting of F, Cl, CH₃, CHF₂, CF₃, OH, OCH₃, OCHF₂,OCF₃, and —CN;

-   -   A¹ is H, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionally        substituted with up to six fluorine atoms, Cl, —CN, OCH₃, OCHF₂,        or OCF₃;    -   A² is C₍₁₋₆₎alkyl, C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl,

CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, or CH₂—CCH; wherein said C₍₁₋₆₎alkyl, andsaid C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl are optionally substituted with up tosix fluorine atoms, Cl, —CN, OCH₃, OCHF₂, or OCF₃;

-   -   or A¹ and A² may be taken together with their attached nitrogen        to form a ring selected from the group consisting of:    -   thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,        morpholinyl, azetidinyl, and aziridinyl; wherein said        piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, azetidinyl,        and aziridinyl are optionally substituted with CF₃, CHF₂, CH₂F,        CH₂CH₂F, C₍₁₋₂₎alkyl, C₍₃₋₆₎cycloalkyl, —CN, OH, CH₂OH, F, Cl,        OCH₃, OCHF₂, OCF₃, —(CX₂)_(n)O(CX₂)_(n)—, or —(CX₂)_(n)— and up        to three additional substituents selected from the group        consisting of CH₃, and F;        -   wherein n is independently 0, 1, 2, 3, or 4;        -   X is H, or F; wherein each occurrence of X in a single            molecule is independently defined;

R⁵ is SO₂NA³A⁴, CONA³A⁴, NA³A⁴, or C₍₁₋₆₎alkyl; wherein said C₍₁₋₆₎alkylis optionally substituted with OH, Cl, —CN, OCH₃, OCHF₂, OCF₃, NA³A⁴, orcyclopropyl, and up to six fluorine atoms;

-   -   A³ is H, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionally        substituted with OH, Cl, —CN, OCH₃, OCHF₂, or OCF₃; and up to        six fluorine atoms;    -   A⁴ is C₍₁₋₆₎alkyl, C₍₃₋₆₎cycloalkyl, or C₍₃₋₆₎heterocycloalkyl;        wherein said C₍₁₋₆₎alkyl is optionally substituted with        cyclopropyl, morpholinyl, OH, OCH₃, C(O)NH₂, Cl, —CN, OCHF₂,        OCF₃ and additionally substituted with up to three fluorine        atoms; and wherein said C₍₃₋₆₎cycloalkyl, and        C₍₃₋₆₎heterocycloalkyl are optionally substituted with CF₃, CH₃,        —CN, C(O)NH₂, and up to three fluorine atoms;    -   or A³ and A⁴ can be taken together with their attached nitrogen        to form a ring selected from the group consisting of azetidinyl,        piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and        aziridinyl wherein said azetidinyl, piperidinyl, morpholinyl,        piperazinyl pyrrolidinyl, and aziridinyl are optionally        substituted with up to four groups selected from the group        consisting of CF₃, OH, CH₃, CH₂F, and CHF₂; and further        optionally substituted with up to six fluorine atoms;

R⁷ is H, F, OH, OCH₃, CH₃, CHF₂, CH₂F, or CF₃;

R⁸ is H, or F; or if R⁴ is H, then R⁷ and R⁸ may be taken together toform a C₍₃₋₆₎cycloalkyl ring; and pharmaceutically acceptable saltsthereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises compounds of Formula I:

wherein

is phenyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazyl;

R¹ is H, Cl, OCF₃, C₍₁₋₄₎alkyl (including C₍₁₋₃₎alkyl), —CN, F,OC₍₁₋₄₎alkyl (including C₍₁₋₃₎alkyl), OCHF₂, Br, I, or cyclopropyl;wherein said C₍₁₋₄₎alkyl is optionally substituted with up to sixfluorine atoms;

R² is H, F, Cl, —CN, OC₍₁₋₄₎alkyl, OCHF₂, OCF₃, cyclopropyl, orC₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionally substituted with upto five fluorine atoms, and said cyclopropyl is optionally substitutedwith OH, CH₃, CF₃, —CN, and up to five fluorine atoms; or R¹ and R² maybe taken together with their attached ring A to form a fused ring systemselected from the group consisting of naphthalenyl, isoquinolinyl,tetrahydronaphthalenyl, quinolinyl, 2,3-dihydro-1H-indenyl, chromanyl,isochromanyl, and naphthyridinyl; wherein said naphthalenyl,isoquinolinyl, tetrahydronaphthalenyl, quinolinyl,2,3-dihydro-1H-indenyl, chromanyl, isochromanyl, and naphthyridinyl areoptionally substituted up to three times with F, C₍₁₋₃₎alkyl, orOC₍₁₋₃₎alkyl; wherein each substituent is selected independently;wherein said OC₍₁₋₃₎alkyl and C₍₁₋₃₎ alkyl is optionally substitutedwith up to five fluorine atoms; provided that R² may not be H if R¹ isH;

R³ is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl,pyridyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, orfuranyl; wherein said oxadiazolyl, thiazolyl, thiadiazolyl,isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, pyridyl,pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, or furanyl isoptionally substituted with R⁶, and further optionally substituted withone substituent selected from the group consisting of F, CH₃, and CF₃;

-   -   R⁶ is

C₍₁₋₆₎alkyl, C(O)NH₂, —CN, C₍₃₋₆₎cycloalkyl, NH₂, NH(C₍₁₋₆₎alkyl),N(C₍₁₋₆₎alkyl)₂, NHCO(C₍₁₋₆₎alkyl), N(C₍₁₋₆₎alkyl)CO(C₍₁₋₆₎alkyl),NHSO₂(C₍₁₋₆₎alkyl), N(C₍₁₋₆₎alkyl)SO₂(C₍₁₋₆₎alkyl), O(C₍₁₋₆₎alkyl),C(O)NH₂, CONH(C₍₁₋₆₎alkyl), CON(C₍₁₋₆₎alkyl)₂, SO₂NH₂,SO₂NH(C₍₁₋₆₎alkyl), SO₂NH(COC₍₁₋₆₎alkyl), or SO₂N(C₍₁₋₆₎alkyl)₂; whereinsaid C₍₁₋₆₎alkyl or C₍₃₋₆₎cycloalkyl is optionally independentlysubstituted with up to six fluorine atoms, CO₂H, OH, —CN, C(O)NH₂, NH₂,OCH₃, OCHF₂, OCF₃, —(CX₂)_(m)—, or N(CH₃)₂;

-   -   -   wherein m is 2, 3, 4, or 5;        -   X is H, or F; wherein each occurrence of X in a single            molecule is independently defined;

R⁴ is H, C₍₃₋₈₎cycloalkyl, C₍₃₋₈₎alkyl, OC₍₁₋₈₎alkyl, phenyl, pyridyl,CH₂SO₂C₍₁₋₃₎alkyl, NA¹A², CH₂O—C₍₃₋₈₎alkyl, O—C₍₃₋₈₎cycloalkyl,tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, oxadiazolyl,isoxadiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrimidyl,pyridazyl, pyrazyl, imidazolyl, pyrrolyl, or furanyl, wherein saidC₍₃₋₈₎alkyl and O—C₍₃₋₈₎alkyl are optionally substituted with 1 to 4substituents independently selected from F, Cl, OH, OCH₃, OCHF₂, OCF₃,and —CN; and said C₍₃₋₈₎cycloalkyl, O—C₍₃₋₈₎cycloalkyl,tetrahydrofuranyl, tetrahydropyranyl, phenyl, thiadiazolyl, oxadiazolyl,isoxadiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl,pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, and furanyl areoptionally substituted with 1 to 4 substituents independently selectedfrom the group consisting of F, Cl, CH₃, CHF₂, CF₃, OH, OCH₃, OCHF₂,OCF₃, and —CN;

-   -   A¹ is H, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionally        substituted with up to six fluorine atoms, Cl, —CN, OCH₃, OCHF₂,        or OCF₃;    -   A² is C₍₁₋₆₎alkyl, C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl,

CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, or CH₂—CCH; wherein said C₍₁₋₆₎alkyl, andsaid C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl are optionally substituted with up tosix fluorine atoms, Cl, —CN, OCH₃, OCHF₂, or OCF₃;

-   -   or A¹ and A² may be taken together with their attached nitrogen        to form a ring selected from the group consisting of:    -   thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,        morpholinyl, azetidinyl, and aziridinyl; wherein said        piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, azetidinyl,        and aziridinyl are optionally substituted with CF₃, CHF₂, CH₂F,        CH₂CH₂F, C₍₁₋₂₎alkyl, C₍₃₋₆₎cycloalkyl, —CN, OH, CH₂OH, F, Cl,        OCH₃, OCHF₂, OCF₃, —(CX₂)_(n)O(CX₂)_(n)—, or —(CX₂)_(n)— and up        to three additional substituents selected from the group        consisting of CH₃,

and F (including

-   -   -   wherein n is independently 0, 1, 2, 3, or 4;        -   X is H, or F; wherein each occurrence of X in a single            molecule is independently defined;

R⁵ is SO₂NA³A⁴, CONA³A⁴ (including

NA³A⁴, or C₍₁₋₆₎alkyl; wherein said C₍₁₋₆₎alkyl is optionallysubstituted with OH, Cl, —CN, OCH₃, OCHF₂, OCF₃, NA³A⁴, or cyclopropyl,and up to six fluorine atoms;

-   -   A³ is H, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionally        substituted with OH, Cl, —CN, OCH₃, OCHF₂, or OCF₃; and up to        six fluorine atoms;    -   A⁴ is C₍₁₋₆₎alkyl, C₍₃₋₆₎cycloalkyl, or C₍₃₋₆₎heterocycloalkyl;        wherein said C₍₁₋₆₎alkyl is optionally substituted with        cyclopropyl, morpholinyl, OH, OCH₃, C(O)NH₂, Cl, —CN, OCHF₂,        OCF₃ and additionally substituted with up to three fluorine        atoms; and wherein said C₍₃₋₆₎cycloalkyl, and        C₍₃₋₆₎heterocycloalkyl are optionally substituted with CF₃, CH₃,        —CN, C(O)NH₂, and up to three fluorine atoms;    -   or A³ and A⁴ can be taken together with their attached nitrogen        to form a ring selected from the group consisting of azetidinyl,        piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and        aziridinyl wherein said azetidinyl, piperidinyl, morpholinyl,        piperazinyl pyrrolidinyl, and aziridinyl are optionally        substituted with up to four groups selected from the group        consisting of CF₃, OH, CH₃, CH₂F, and CHF₂; and further        optionally substituted with up to six fluorine atoms;

R⁷ is H, F, OH, OCH₃, CH₃, CHF₂, CH₂F, or CF₃;

R⁸ is H, or F; or if R⁴ is H, then R⁷ and R⁸ may be taken together toform a C₍₃₋₆₎cycloalkyl ring; and pharmaceutically acceptable saltsthereof.

In another embodiment of the invention:

-   -   Z is N, or CH; R¹ is H, Cl, OCF₃, C₍₁₋₃₎alkyl, —CN, F,        OC₍₁₋₃₎alkyl, OCHF₂, Br, I, or cyclopropyl; wherein said        C₍₁₋₃₎alkyl is optionally substituted with up to five fluorine        atoms;

R² is H, F, Cl, —CN, OCH₃, OCHF₂, OCF₃, cyclopropyl, or C₍₁₋₄₎alkyl;wherein said C₍₁₋₄₎alkyl is optionally substituted with up to fivefluorine atoms (including CF₃, and CHF₂), and said cyclopropyl isoptionally substituted with OH, CH₃, CF₃, —CN, and up to five fluorineatoms; or R¹ and R² may be taken together with their attached ring A toform a fused ring system selected from the group consisting ofnaphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl,wherein said naphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, andquinolinyl are optionally substituted with F, CHF₂, CH₂F, CF₃, or CH₃;provided that R² may not be H if R¹ is H;

R³ is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl,pyridyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, or pyrrolyl; whereinsaid oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl,imidazolyl, or pyrrolyl is optionally substituted with R⁶;

-   -   R⁶ is

C₍₁₋₄₎alkyl (including C₍₁₋₂₎alkyl), C(O)NH₂, or —CN; wherein saidC₍₁₋₄₎alkyl is optionally substituted with up to six fluorine atoms,CO₂H, OH, or —CN (including CH₂C(CH₃)₂CO₂H, CH₂C(CH₃)₂CN, andC₍₁₋₆₎alkylC(CH₃)₂OH);

R⁴ is C₍₃₋₆₎cycloalkyl, isopropyl, C(CH₃)₂OCH₃, OC₍₁₋₄₎alkyl,fluorophenyl, difluorophenyl, pyridyl, CH₂SO₂CH₃, or NA¹A², wherein saidC₍₃₋₆₎cycloalkyl is optionally substituted with OCH₃, two fluoro groupsor two methyl groups;

-   -   A¹ is H, or C₍₁₋₃₎alkyl; wherein said C₍₁₋₃₎alkyl is optionally        substituted with up to five fluorine atoms, Cl, —CN, OCH₃,        OCHF₂, or OCF₃;    -   A² is C₍₁₋₄₎alkyl, C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl,        CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, or CH₂—CCH; wherein said C₍₁₋₄₎alkyl,        and said C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl are optionally substituted        with up to three fluorine atoms, Cl, —CN, OCH₃, OCHF₂, or OCF₃        (including CH₂CH₂—CN);    -   or A¹ and A² may be taken together with their attached nitrogen        to form a ring selected from the group consisting of:

-   -   thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and        morpholinyl; wherein said piperidinyl, pyrrolidinyl,        piperazinyl, and morpholinyl are optionally substituted with        CF₃, CH₂F, CH₂CH₂F, C₍₁₋₂₎alkyl, —CN, OH, CH₂OH, F, Cl, OCH₃,        OCHF₂, or OCF₃, and up to three additional substituents selected        from the group consisting of CH₃, and F;

R⁵ is SO₂NA₃A₄, C₍₁₋₆₎alkyl,

wherein said C₍₁₋₆₎alkyl is optionally substituted with OH, Cl, —CN,OCH₃, OCHF₂, OCF₃, or NA³A⁴; and up to six fluorine atoms;

-   -   A³ is H, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionally        substituted with OH, Cl, —CN, OCH₃, OCHF₂, or OCF₃; and up to        six fluorine atoms;    -   A₄ is C₍₁₋₆₎alkyl, C₍₃₋₆₎cycloalkyl (including cyclopropyl, and        cyclobutyl), oxetanyl, or tetrahydrofuranyl; wherein said        C₍₁₋₆₎alkyl is optionally substituted with cyclopropyl,        morpholinyl, OH, OCH₃, or C(O)NH₂, and additionally substituted        with up to three fluorine atoms; and wherein said        C₍₃₋₆₎cycloalkyl, oxetanyl, and tetrahydrofuranyl are optionally        substituted with CF₃, CH₃, —CN, or C(O)NH₂;    -   or A³ and A⁴ can be taken together with their attached nitrogen        to form a ring selected from the group consisting of azetidinyl,        piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl wherein        said azetidinyl, piperidinyl, morpholinyl, and piperazinyl are        optionally substituted with up to four groups selected from the        group consisting of CF₃, OH, and CH₃; and further optionally        substituted with up to six fluorine atoms;

R⁷ is H, F, OH, or OCH₃;

R⁸ is H;

and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

-   -   Z is N, or CH;

R¹ is H, Cl, OCF₃, C₍₁₋₃₎alkyl, —CN, F, OC₍₁₋₃₎alkyl, OCHF₂, orcyclopropyl, wherein said C₍₁₋₂₎alkyl is optionally substituted with upto five fluorine atoms (including CHF₂, and CF₃);

R² is CHF₂, CF₃, H, F, Cl, —CN,

or R¹ and R² may be taken together with their attached ring A to form afused ring system selected from the group consisting of naphthalenyl,isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl, wherein saidnaphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl areoptionally substituted with F, CHF₂, CH₂F, CF₃, or CH₃; provided that R²may not be H if R¹ is H;

R³ is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl,pyridyl, pyrimidyl, pyridazyl, or pyrazyl; wherein said oxadiazolyl,thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl, oxazolyl,triazolyl, pyridyl, pyrimidyl, pyridazyl, or pyrazyl is optionallysubstituted with R⁶;

-   -   R⁶ is

C₍₁₋₂₎alkyl (including CH₃), CH₂C(CH₃)₂CO₂H, C₍₀₋₁₎alkylC(CH₃)₂OH,CH₂C(CH₃)₂CN, C(O)NH₂, or —CN; wherein said C₍₁₋₂₎alkyl is optionallysubstituted with up to five fluorine atoms;

R⁴ is C₍₃₋₆₎cycloalkyl, isopropyl, C(CH₃)₂OCH₃, OC₍₁₋₄₎alkyl (includingOC(CH₃)₃ and OCH(CH₃)₂), fluorophenyl, difluorophenyl, pyridyl,CH₂SO₂CH₃, or NA¹A², wherein said C₍₃₋₆₎cycloalkyl is optionallysubstituted with OCH₃, two fluoro groups or two methyl groups;

-   -   A¹ is H, or C₍₁₋₃₎alkyl; wherein said C₍₁₋₃₎alkyl is optionally        substituted with up to five fluorine atoms (including CH₂CH₂F);    -   A² is C₍₁₋₄₎alkyl (including C₍₂₋₄₎alkyl),        C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl (including CH₂-cyclopentyl,        CH₂CH₂-cyclopropyl, C₍₃₋₄₎cycloalkyl, and

CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, CH₂—CCH, or CH₂CH₂—CN; wherein saidC₍₁₋₄₎alkyl, and said C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl are optionallysubstituted with up to three fluorine atoms;

-   -   or A¹ and A² may be taken together with their attached nitrogen        to form a ring selected from the group consisting of:

-   -   thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and        morpholinyl; wherein said piperidinyl, pyrrolidinyl,        piperazinyl, and morpholinyl are optionally substituted with

CF₃, CH₂F, CH₂CH₂F, C₍₁₋₂₎alkyl, —CN, OH, CH₂OH, or F, and up to threeadditional substituents selected from the group consisting of CH₃, andF;

R⁵ is SO₂NA₃A₄, C₍₁₋₆₎alkyl,

wherein said C₍₁₋₆₎alkyl is optionally substituted with OH, OCH₃, orNA³A⁴; and up to six fluorine atoms (including C(CF₃)₂OH);

-   -   A³ is H, or C₍₁₋₄₎alkyl (including CH₃CH₂, and C(CH₃)₃);    -   A₄ is C₍₁₋₆₎alkyl, cyclopropyl, cyclobutyl, oxetanyl, or        tetrahydrofuranyl; wherein said C₍₁₋₆₎alkyl is optionally        substituted with cyclopropyl, morpholinyl, OH, OCH₃, or C(O)NH₂,        and additionally substituted with up to three fluorine atoms        (including C(CH₃)₂CH₂OCH₃, C(CH₃)₂CH₂OH, C(CH₃)₂CH₂-morpholinyl,        C(CH₃)₂CH₂CH₂OH, C(CH₃)₂CH₂C(O)NH₂, and CH₂C(CH₃)₂OH); and        wherein said cyclopropyl cyclobutyl, oxetanyl, and        tetrahydrofuranyl are optionally substituted with CF₃, CH₃, —CN,        or C(O)NH₂;    -   or A³ and A⁴ can be taken together with their attached nitrogen        to form a ring selected from the group consisting of azetidinyl,        piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl wherein        said azetidinyl, piperidinyl, morpholinyl, and piperazinyl are        optionally substituted with up to two groups selected from the        group consisting of CF₃, OH, and CH₃; and further optionally        substituted with up to three fluorine atoms;

R⁷ is H, F, OH, or OCH₃;

R⁸ is H;

and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

Z is N, or CH;

R¹ is H, Cl, OCF₃, CF₃, CHF₂, C₍₁₋₃₎alkyl (including CH₂CH₃), —CN, F,OC₍₁₋₃₎alkyl (including OCH₃), or OCHF₂;

R² is CHF₂, CF₃, H, F, Cl,

or R¹ and R² may be taken together with their attached ring A to form afused ring system selected from the group consisting of naphthalenyl,isoquinolinyl, and tetrahydronaphthalenyl; provided that R² may not be Hif R¹ is H;

R³ is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl,pyridyl, or pyrimidyl, wherein said oxadiazolyl, thiazolyl,thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl,pyridyl or pyrimidyl is optionally substituted with R⁶;

-   -   R⁶ is

CH₃, CH₂C(CH₃)₂CO₂H, C₍₁₋₆₎alkylC(CH₃)₂OH (including C(CH₃)₂OH),CH₂C(CH₃)₂CN, or C(O)NH₂;

R⁴ is C₍₃₋₆₎cycloalkyl (including C₍₄₋₆₎cycloalkyl), isopropyl,C(CH₃)₂OCH₃, OCH(CH₃)₂, OC(CH₃)₃, fluorophenyl, difluorophenyl, orNA¹A², wherein said C₍₃₋₆₎cycloalkyl is optionally substituted withOCH₃, two fluoro groups or two methyl groups;

-   -   A¹ is H, C₍₁₋₃₎alkyl (including CH₂CH₃), or CH₂CH₂F;

A² is C₍₂₋₄₎alkyl (including CH₂CH₃), CH₂-cyclopentyl,CH₂CH₂-cyclopropyl, C₍₃₋₄₎cycloalkyl,

CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, CH₂—CCH, or CH₂CH₂—CN; wherein saidC₍₃₋₄₎cycloalkyl is optionally substituted with one fluorine atom andsaid C₍₂₋₄₎alkyl is optionally substituted with up to three fluorineatoms (including CH₂CF₃);or A¹ and A² may be taken together with their attached nitrogen to forma ring selected from the group consisting of:

thiomorpholinyl, piperidinyl, pyrrolidinyl, and morpholinyl; whereinsaid piperidinyl, and pyrrolidinyl are optionally substituted with CF₃,CH₂F, CH₂CH₂F, C₍₁₋₂₎alkyl (including CH₃), —CN, OH, or CH₂OH, and up tothree additional substituents selected from the group consisting of CH₃,and F (including difluoropiperidinyl, fluoropiperidinyl);

R⁵ is SO₂NA₃A₄, C(CF₃)₂OH,

-   -   A³ is H, CH₃CH₂, or C(CH₃)₃;    -   A⁴ is C₍₁₋₆₎alkyl (including C(CH₃)₃),

C(CH₃)₂CH₂OCH₃, C(CH₃)₂CH₂OH, C(CH₃)₂CH₂-morpholinyl, C(CH₃)₂CH₂CH₂OH,C(CH₃)₂CH₂C(O)NH₂, or CH₂C(CH₃)₂OH; wherein said C₍₁₋₆₎alkyl isoptionally substituted with up to three fluorine atoms;or A³ and A⁴ can be taken together with their attached nitrogen to forma ring selected

-   -   from the group consisting of

R⁷ is H;

R⁸ is H;

and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

-   -   Z is N, or CH;

R¹ is H, Cl, OCF₃, CF₃, CHF₂, or F;

R² is CHF₂, CF₃, H, F, Cl,

or R¹ and R² may be taken together with their attached ring A to form afused ring system selected from the group consisting of naphthalenyl,and isoquinolinyl; provided that R² may not be H if R¹ is H;

R³ is

or phenyl, wherein said phenyl is optionally substituted with R⁶;

-   -   R⁶ is CH₃, CH₂C(CH₃)₂CO₂H, or C(CH₃)₂OH;

R⁴ is C₍₄₋₆₎cycloalkyl, isopropyl, C(CH₃)₂OCH₃, OCH(CH₃)₂,difluoropiperidinyl, fluoropiperidinyl, fluorophenyl, or NA¹A², whereinsaid C₍₄₋₆₎cycloalkyl is optionally substituted with OCH₃, two fluorogroups or two methyl groups; and wherein A¹ and A² are taken togetherwith their attached nitrogen to form a pyrrolidinyl ring, wherein saidpyrrolidinyl ring is optionally substituted with CH₃, CH₂F, and up tothree additional substituents selected from the group consisting of CH₃,and F;

R⁵ is SO₂NA₃A₄, C(CF₃)₂OH,

-   -   A³ is H;

A⁴ is

or C(CH₃)₃;

R⁷ is H;

R⁸ is H;

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention is a compound selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention is a compound selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention comprises a compound of Formula Iand a pharmaceutically acceptable carrier.

The present invention also provides a method for preventing, treating orameliorating an RORγt mediated inflammatory syndrome, disorder ordisease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of preventing, treating orameliorating a syndrome, disorder or disease, wherein said syndrome,disorder or disease is selected from the group consisting of: ophthalmicdisorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis,psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn'sDisease, ulcerative colitis, ankylosing spondylitis, nephritis, organallograft rejection, fibroid lung, cystic fibrosis, renal insufficiency,diabetes and diabetic complications, diabetic nephropathy, diabeticretinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis,chronic obstructive pulmonary disease, sarcoidosis, invasivestaphylococcia, inflammation after cataract surgery, allergic rhinitis,allergic conjunctivitis, chronic urticaria, systemic lupuserythematosus, asthma, allergic asthma, steroid resistant asthma,neutrophilic asthma, periodontal diseases, periodonitis, gingivitis, gumdisease, diastolic cardiomyopathies, cardiac infarction, myocarditis,chronic heart failure, angiostenosis, restenosis, reperfusion disorders,glomerulonephritis, solid tumors and cancers, chronic lymphocyticleukemia, chronic myelocytic leukemia, multiple myeloma, malignantmyeloma, Hodgkin's disease, and carcinomas of the bladder, breast,cervix, colon, lung, prostate, or stomach comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, Crohn's disease, and ulcerative colitis.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, Crohn's disease, and ulcerative colitiscomprising administering to a subject in need thereof an effectiveamount of a compound of Formula I or a form, composition or medicamentthereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: inflammatory boweldiseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonarydisorder, psoriatic arthritis, ankylosing spondylitis, neutrophilicasthma, steroid resistant asthma, multiple sclerosis, and systemic lupuserythematosus comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,and psoriasis comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, in a subject in need thereof comprisingadministering to the subject an effective amount of the compound ofFormula I or composition or medicament thereof in a combination therapywith one or more anti-inflammatory agents, or immunosuppressive agents,wherein said syndrome, disorder or disease is selected from the groupconsisting of: rheumatoid arthritis, and psoriasis.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is rheumatoid arthritis, comprising administering to a subjectin need thereof an effective amount of a compound of Formula I or aform, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is psoriasis comprising administering to a subject in needthereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is chronic obstructive pulmonary disorder comprisingadministering to a subject in need thereof an effective amount of acompound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is psoriatic arthritis comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is ankylosing spondylitis comprising administering to a subjectin need thereof an effective amount of a compound of Formula I or aform, composition or medicament thereof.

The present invention provides a method of treating or ameliorating aninflammatory bowel disease, wherein said inflammatory bowel disease isCrohn's disease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating aninflammatory bowel disease, wherein said inflammatory bowel disease isulcerative colitis comprising administering to a subject in need thereofan effective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is neutrophilic asthma comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is steroid resistant asthma comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is multiple sclerosis comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is systemic lupus erythematosus comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The invention also relates to methods of modulating RORγt activity in amammal by administration of an effective amount of at least one compoundof Formula I.

DEFINITIONS

The term “administering” with respect to the methods of the invention,means a method for therapeutically or prophylactically preventing,treating or ameliorating a syndrome, disorder or disease as describedherein by using a compound of Formula I or a form, composition ormedicament thereof. Such methods include administering an effectiveamount of said compound, compound form, composition or medicament atdifferent times during the course of a therapy or concurrently in acombination form. The methods of the invention are to be understood asembracing all known therapeutic treatment regimens.

The term “subject” refers to a patient, which may be an animal,typically a mammal, typically a human, which has been the object oftreatment, observation or experiment and is at risk of (or susceptibleto) developing a syndrome, disorder or disease that is associated withabberant RORγt expression or RORγt overexpression, or a patient with aninflammatory condition that accompanies syndromes, disorders or diseasesassociated with abberant RORγt expression or RORγt overexpression.

The term “effective amount” means that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue system, animal or human, that is being sought by aresearcher, veterinarian, medical doctor, or other clinician, whichincludes preventing, treating or ameliorating the symptoms of asyndrome, disorder or disease being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The term “alkyl” refers to both linear and branched chain radicals of upto 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwiseindicated, and includes, but is not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl and dodecyl. Any alkyl group may be optionally substituted withone OCH₃, one OH, or up to two fluorine atoms.

The term “C_((a-b))” (where a and b are integers referring to adesignated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl,alkoxy or cycloalkyl radical or to the alkyl portion of a radical inwhich alkyl appears as the prefix root containing from a to b carbonatoms inclusive. For example, C₍₁₋₄₎ denotes a radical containing 1, 2,3 or 4 carbon atoms.

The term “cycloalkyl” refers to a saturated or partially unsaturatedmonocyclic or bicyclic hydrocarbon ring radical derived by the removalof one hydrogen atom from a single ring carbon atom. Typical cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Additionalexamples include C₍₃₋₆₎cycloalkyl, C₍₅₋₈₎cycloalkyl,decahydronaphthalenyl, and 2,3,4,5,6,7-hexahydro-1H-indenyl.

Any cycloalkyl group may be optionally substituted with one OCH₃, oneOH, or up to two fluorine atoms.

The term “heterocycloalkyl” refers to a saturated or partiallyunsaturated monocyclic or bicyclic hydrocarbon ring radical containingat least one ring atom selected from the group consisting O, N, or S,derived by the removal of one hydrogen atom from a single ring carbonatom or nitrogen atom. Typical heterocycloalkyl radicals includeazetidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,oxetanyl and tetrahydrofuranyl. Sulfur atoms in the ring of theheterocycloalkyl group may be in any oxidation state.

As used herein, the term “thiophenyl” is intended to describe theradical formed by removing a hydrogen atom from the molecule with thestructure:

Whenever a variable, such as “n” in —(CX₂)_(n)O(CX₂)_(n)—, appears morethan one time in a chemical formula, each definition is considered to beindependent.

Where an alkyl substituent, such as but not limited to C₍₁₋₆₎alkyl,appears more than once in a compound of Formula I, each substitution onsaid alkyl group is independently selected.

An alkyl group may be substituted as described in the specification.When an alkyl group is substituted with the diradical —(CX₂)_(m)— bothtermini of the diradical may be attached to either the same or differentcarbon atoms. For example, both

are examples of —(CX₂)_(m)— substitution on a butyl group. Examples of—(CX₂)_(m)— substitution include without limitation

Similarly, —(CX₂)_(n)—, or —(CX₂)_(n)O(CX₂)_(n)— diradical substitutionmay occur on either the same or different ring carbons. Examples of—(CX₂)_(n)— substitution include without limitation

Examples of —(CX₂)_(n)O(CX₂)_(n)— substitution include withoutlimitation

Pharmaceutically Acceptable Salts

Pharmaceutically acceptable acidic/anionic salts include, and are notlimited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,bromide, calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate and triethiodide. Organic orinorganic acids also include, and are not limited to, hydriodic,perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, saccharinic or trifluoroacetic acid.

Pharmaceutically acceptable basic/cationic salts include, and are notlimited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (alsoknown as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”),ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calciumhydroxide, chloroprocaine, choline, choline bicarbonate, cholinechloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium,LiOMe, L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine,piperidine, potassium, potassium-t-butoxide, potassium hydroxide(aqueous), procaine, quinine, sodium, sodium carbonate,sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

Methods of Use

The present invention is directed to a method for preventing, treatingor ameliorating a RORγt mediated inflammatory syndrome, disorder ordisease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

Since RORγt is an N-terminal isoform of RORγ, it is recognized thatcompounds of the present invention which are modulators of RORγt arelikely to be modulators of RORγ as well. Therefore the mechanisticdescription “RORγt modulators” is intended to encompass RORγ modulatorsas well.

When employed as RORγt modulators, the compounds of the invention may beadministered in an effective amount within the dosage range of about 0.5mg to about 10 g, preferably between about 0.5 mg to about 5 g, insingle or divided daily doses. The dosage administered will be affectedby factors such as the route of administration, the health, weight andage of the recipient, the frequency of the treatment and the presence ofconcurrent and unrelated treatments.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for compounds of the present invention or apharmaceutical composition thereof will vary according to the desiredeffect. Therefore, optimal dosages to be administered may be readilydetermined by one skilled in the art and will vary with the particularcompound used, the mode of administration, the strength of thepreparation, and the advancement of the disease condition. In addition,factors associated with the particular subject being treated, includingsubject age, weight, diet and time of administration, will result in theneed to adjust the dose to an appropriate therapeutic level. The abovedosages are thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

The compounds of Formula I may be formulated into pharmaceuticalcompositions comprising any known pharmaceutically acceptable carriers.Exemplary carriers include, but are not limited to, any suitablesolvents, dispersion media, coatings, antibacterial and antifungalagents and isotonic agents. Exemplary excipients that may also becomponents of the formulation include fillers, binders, disintegratingagents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts which are formed from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, benzoate,benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride,hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate,pivalate, propionate, succinate, sulfate and tartrate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamino salts and salts withamino acids such as arginine. Also, the basic nitrogen-containing groupsmay be quaternized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered byany means that accomplish their intended purpose. Examples includeadministration by parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, buccal or ocular routes. Alternatively orconcurrently, administration may be by the oral route. Suitableformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form, for example, water-solublesalts, acidic solutions, alkaline solutions, dextrose-water solutions,isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

The present invention also encompasses a method of making apharmaceutical composition comprising mixing a pharmaceuticallyacceptable carrier with any of the compounds of the present invention.Additionally, the present invention includes pharmaceutical compositionsmade by mixing a pharmaceutically acceptable carrier with any of thecompounds of the present invention.

Polymorphs and Solvates

Furthermore, the compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, the compounds mayform solvates, for example with water (i.e., hydrates) or common organicsolvents. As used herein, the term “solvate” means a physicalassociation of the compounds of the present invention with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. The term “solvate” is intended to encompass bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

It is intended that the present invention include within its scopepolymorphs and solvates of the compounds of the present invention. Thus,in the methods of treatment of the present invention, the term“administering” shall encompass the means for treating, ameliorating orpreventing a syndrome, disorder or disease described herein with thecompounds of the present invention or a polymorph or solvate thereof,which would obviously be included within the scope of the inventionalbeit not specifically disclosed.

In another embodiment, the invention relates to a compound as describedin Formula I for use as a medicament.

In another embodiment, the invention relates to the use of a compound asdescribed in Formula I for the preparation of a medicament for thetreatment of a disease associated with an elevated or aberrant RORγtactivity.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, Ed. H. Bundgaard, Elsevier, 1985.

Furthermore, it is intended that within the scope of the presentinvention, any element, in particular when mentioned in relation to acompound of Formula I, shall comprise all isotopes and isotopic mixturesof said element, either naturally occurring or synthetically produced,either with natural abundance or in an isotopically enriched form. Forexample, a reference to hydrogen includes within its scope ¹H, ²H (D),and ³H (T). Similarly, references to carbon and oxygen include withintheir scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopesmay be radioactive or non-radioactive. Radiolabelled compounds ofFormula I may comprise a radioactive isotope selected from the group of³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br.Preferably, the radioactive isotope is selected from the group of ³H,¹¹C and ¹⁸F.

Some compounds of the present invention may exist as atropisomers.Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the steric strain barrier to rotation is high enoughto allow for the isolation of the conformers. It is to be understoodthat all such conformers and mixtures thereof are encompassed within thescope of the present invention.

Where the compounds according to this invention have at least one stereocenter, they may accordingly exist as enantiomers or diastereomers. Itis to be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

ABBREVIATIONS

Herein and throughout the application, the following abbreviations maybe used.

-   Ac acetyl-   APCI atmospheric pressure chemical ionisation-   br broad-   Bu butyl-   Cy cyclohexyl-   d doublet-   dba dibenzylideneacetone-   DABCO 1,4-diazabicyclo[2.2.2]octane-   DAST diethylaminosulfur trifluoride-   DCM dichloromethane-   DIPEA N,N-diisopropylethylamine (Hunigs base)-   DMA dimethylacetamide-   DMAP 4-dimethylaminopyridine-   DME ethylene glycol dimethyl ether-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   dppf 1,1′-bis(diphenylphosphanyl) ferrocene-   EDC.HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   ESI electrospray ionization-   Et ethyl-   Et₂O diethyl ether-   EtOAc ethyl acetate-   FCC flash column chromatography-   h hour-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxybenzotriazole-   HPLC high pressure liquid chromatography-   Hz Hertz-   IBX 2-iodoxybenzoic acid-   Lawesson Reagent    2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane-   LDA lithium diisopropyl amide-   m multiplet-   M molar (moles/liter)-   Me methyl-   min minutes-   Ms methane sulfonyl-   MS mass spectrometry-   MTBE methyl tert-butyl ether-   NBS N-bromosuccinimide-   NMR nuclear magnetic resonance-   PE petroleum ether-   Ph phenyl-   pin pinacolato-   Piv pivaloyl (Me₃CO)-   ppm parts per million-   psi pounds per square inch-   q quartet-   rt room temperature-   s singlet-   SEM 2-(trimethylsilyl)ethoxymethyl-   t triplet-   TBAF tetrabutylammonium fluoride-   TBAI tetrabutylammonium iodide-   TEA triethylamine-   TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-   Tf trifluoromethanesulfonyl-   TFAA trifluoroacetic acid anhydride-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMS trimethylsilyl-   Ts p-toluenesulfonyl

General Schemes

The compounds of the present invention can be prepared by a combinationof methods known in the art including the procedures described inSchemes I to XII below. The following reaction schemes are only meant torepresent examples of the invention and are in no way meant to be alimit of the invention.

Scheme I describes the preparation of [1,3,4]-oxadiazoles and[1,3,4]-thiadiazoles of the present invention. α-Brominated ketones A-Ican by cyclised using ethyl 2-amino-2-thioxoacetate to give thiazoleintermediates A-II as described in WO2013/178362. Subsequent treatmentwith hydrazine followed by coupling to carboxylic acids R⁶COOH andcyclization with, e.g., TsCl or Tf₂O, affords the [1,3,4]-oxadiazoleintermediates A-III (X═H). This sequence can alternatively be applied toa brominated A-II, which requires a bromination step prior to hydrazideformation. Pd catalyzed coupling with an appropriate aryl halide or arylboronic ester (in case of a Suzuki procedure) affords compounds ofstructure A-IV. Intermediates A-III can be preapared by an alternativeroute that uses a different order of steps. Reaction of intermediatessuch as A-VIII with hydrazine followed by coupling to carboxylic acidR⁶COOH and cyclization with, e.g., TsCl, affords the [1,3,4]-oxadiazoleintermediates A-IX. Palladium-catalyzed coupling with an appropriatealkyl zinc reagent then affords intermediates A-III. An alternativeroute uses a different order of steps, starting with apalladium-catalyzed coupling of intermediates A-II with an appropriatearyl halide. This is followed by hydrazine treatment, coupling to R⁶COOHand cyclization as previously described to afford intermediates A-IV.[1,3,4]-Thiadiazoles can be prepared in a similar fashion. Reaction ofintermediates A-II with hydrazine followed by coupling to carboxylicacid R⁶COOH and treatment with Lawesson reagent at elevated temperatureaffords [1,3,4]-thiadiazoles A-VI. Palladium-catalyzed coupling with anappropriate aryl halide leads to compounds of structure A-VII.

Scheme II illustrates the preparation of [1,3,4]-oxadiazoles of thepresent invention bearing an amine group NA¹A² as substituent R⁴.1-Bromo-3-hydroxypropan-2-one can be cyclized with ethyl2-amino-2-thioxoacetate to give the thiazole intermediate B-I.Protection using SEMCl is followed by acyl hydrazide formation, R⁶COOHcoupling and cyclization using, e.g., TsCl, to afford intermediatesB-II. Deprotection using HCl is followed by palladium-catalyzed couplingwith an appropriate aryl halide and selective oxidation using, e.g.,MnO₂, to give the aldehyde intermediates B-III. Reductive aminationleads to compounds of structure B-IV. Alternatively B-I can first beconverted to B-V by a sequence of palladium-catalyzed coupling, MnO₂oxidation and reductive amination. Compounds of structure B—IV can beobtained from B—V by applying the same three steps from ester tooxadiazole as described for preparation of B-II.

[1,2,4]-Oxadiazoles of the present invention can be prepared as shown inScheme III. Thiazole ester intermediates A-II can be converted into C-Iusing a sequence of ester ammonolysis, dehydration with TFAA andamidoxime formation with hydroxylamine. The sequence is initiated with abromination step in case of intermediates C-I with X═Br. Acylation ofC-I with R⁶COOH and subsequent cyclization affords the[1,2,4]-oxadiazole intermediates C-II. Palladium-catalyzed couplingusing appropriate aryl halides or aryl boronic acids or esters leads tocompounds of structure C-III. Treatment of brominated thiazoleintermediates A-II with an R⁶ substituted amidoxime results in theformation of [1,2,4]-oxadiazole intermediates C-IV with an R⁶substituent in the 5-position. Suzuki coupling with an appropriate arylboronic acid or ester leads to compounds of structure C-V.

Scheme IV shows the preparation of [1,2,4]-oxadiazoles of the presentinvention bearing an amine group NA¹A² as substituent R⁴. B-I isprotected by using SEMCl followed by ammonolysis, dehydration with TFAAand amidoxime formation using hydroxylamine to give D-I. Acylation withR⁶COOH and cyclization affords intermediates D-II which are deprotected,coupled to an appropriate aryl halide using a palladium catalyst andoxidized with, e.g. MnO₂, to give aldehyde intermediates D-III.Reductive amination leads to compounds of structure D-IV.

The preparation of isoxazoles of the present invention is shown inScheme V. Intermediates A-II can be reduced to alcohols using NaBH₄. IBXoxidation and treatment of the resulting aldehyde with hydroxylamineaffords oxime intermediates E-I. Nitrile oxide formation and [3+2]cycloaddition with an R⁶ substituted alkyne leads to isoxazoles E-II.Palladium-catalyzed coupling with an appropriate aryl halide affordscompounds of structure E-III.

Scheme VI describes the synthesis of 6-membered aryl and heteroarylrings of the present invention. Bromoketones A-I can be cyclized withthiourea to form aminothiazole intermediates, which can then undergoSandmeyer reaction using, e.g., isoamylnitrite and CuBr, to give thebromothiazole intermediates F-I. Suzuki reactions with an appropriatearyl/heteroaryl (U═CH or N) boronic acid or ester gives intermediatesF-II, which in a second palladium-catalyzed reaction with an appropriatearyl halide affords compounds of structure F-III. In an alternativeroute, intermediates A-II are saponified using KOH. After neutralizationwith HCl the resulting carboxylic acids are decarboxylated at rt to giveintermediates F-IV, which are metallated with n-BuLi/ZnCl₂ followed bypalladium-catalyzed coupling to give intermediates F-II.

Scheme VII describes the synthesis of thiazole rings of the presentinvention. Suzuki reaction of intermediates F-I with an appropriate arylboronic acid or ester gives intermediates G-I, which in a secondpalladium-catalyzed reaction with an appropriate aryl halide affordscompounds of structure G-II.

Scheme VIII describes the synthesis of sulfonamide-containing arylbromide intermediates used in the above palladium-catalyzed couplingreactions. Aldehydes H-I are transformed into the anilines of structureH—II by a sequence of fluoronation, reduction, and bromination(R¹═CHF₂). Phenols H-III are transformed by a similar sequence of stepsinto anilines H-II (R¹═OCHF₂). Anilines H-II are treated sodium nitritein acid followed by sulfur dioxide to furnish sulfonyl chlorides H-IV,which are coupled with amines to provide the aryl bromide sulfonamideintermediates H-V. Alternatively bromides H-VI are treated with sulfuricacid then with chlorinating reagents POCl₃ and PCl₅ to afford sulfonylchlorides that are coupled with amines to provide the aryl bromidesulfonamide intermediates H-V. Isoquinolin-1(2H)-one H-VII is firstbrominated then treated with P₂S₅ to furnish4-bromoisoquinoline-1(8H)-thione H-VIII. Subsequent oxidation andsulfonamide formation provides bromide H-IX.

Preparation of the bromo-aryl derivatives I-I, I-VIII, and I-X used inpalladium-catalyzed coupling reactions above are shown in Scheme IX.1,4-Dibromo- or 1-bromo-4-iodo-aromatics I-II can be used as reactantsfor a metallation reactions, e.g. a lithiation with n-butyl-lithium orGrignard formation using isopropyl magnesium chloride. The 1,4-dibromoaromatics should have identical substituents R¹ and R². The metallatedspecies can react with 2,2,2-trifluoro-N-methoxy-N-methylacetamide toform 1-bromo-4-trifluoroacetyl derivates I-III. The trifluoromethylalcohols I-I can be formed by reaction of intermediates I-III withTMSCF₃ in the presence of a fluoride source or by reaction with an alkylGrignard reagent. Alternatively, the metallated species can react withhexafluoroactone to directly form hexafluoroisopropyl alcohols I-I. Theintermediates I-III can also be formed from 1-bromo-4-alkoxycarbonylaromatics I-IV by esterification and subsequent reaction with TMSCF₃ inthe presence of a fluoride source. Alternatively, intermediates I-IIIcan be formed from 1-bromo-4-formyl aromatics I-V by reaction withTMSCF₃ in the presence of a fluoride source and subsequent oxidation.The trifluoromethyl alcohols I-VIII can be formed by reaction ofintermediates I-VII with TMSCF₃ in the presence of a fluoride source.1,3-Dibromoaryl derivatives I-VI can be metallated, e.g. a lithiationwith n-butyl-lithium, and subsequent reaction with the2,2,2-trifluoro-N-methoxy-N-methylacetamide forms1-bromo-3-trifluoroacetyl derivatives I-VII. 1,3-Dibromo arylderivatives I-VI can undergo metallation, e.g. a lithiation withn-butyl-lithium, and subsequent reaction with methyl chloroformate toafford the methyl ester I-IX. Subsequent saponification and amide bondformation furnishes amides I-X.

Scheme X describes the synthesis of bromo-aryl derivatives J-I and J-IV.Methyl ketones J-II can be treated with amines in the presence of areducing agent, e.g. NaHB(OAc)₃, to afford aryl bromides J-I.Alternatively, benzaldehydes J-III can be reduced with sodiumborohydride and subsequently converted to methanesulfonates, which upontreatment with amines furnish intermediates J-IV.

Scheme XI describes the synthesis of some amine intermediates used abovein amide-forming reactions. Compounds K-I and K-III are treated withDAST, and then the tert-butoxycarbonyl groups are removed with HCl toprovide the fluorinated amines K-II and K-IV as hydrochloride salts.

Scheme XII describes the synthesis of boronic esters L-I, L-III, and L-Vused in the above thiazole arylation and heteroarylation reactions.Compounds H-V, L-II, and L-IV are treated with palladium reagents, suchas Pd(dppf)Cl₂, in the presence of bis(pinacolato)diboron to affordboronic esters L-I, L-III, and L-V.

Scheme XIII illustrates the preparation of aryl and heteroaryl halidesM-I, M-III and M-V. Isobutyrate esters can be deprotonated with areagent such as LDA and subsequently reacted with a benzyl bromide toafford compounds of the structure M-I, or with diiodomethane to providecompounds M-II. Subsequent palladium mediated coupling of thecorresponding zinc reagent generated from M-II with symmetricalheteroaryl dihalides, where X can equal Cl or Br and U═N or CH, thengives compounds of the general structure M-III. Lithiation of M-II,using n-BuLi, followed by palladium mediated coupling to 2-bromothiazoleaffords compounds M-IV. Bromination with NBS then yields compounds M-V.

EXAMPLES

Compounds of the present invention can be prepared by methods known tothose who are skilled in the art. The following examples are only meantto represent examples of the invention and are in no way meant to be alimit of the invention.

Intermediate 1: Step a Cyclobutylmethyl 4-methylbenzenesulfonate

To a solution of cyclobutylmethanol (1.00 g, 11.6 mmol) and pyridine(1.4 mL) in DCM (15 mL) was slowly added TsCl (2.44 g, 12.8 mol) at 0°C. The solution was warmed to 20° C. and stirred at that temperature for3 h. The reaction was poured into water (50 mL) and extracted with DCM(2×50 mL). The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness to afford the titlecompound as a colorless oil.

Intermediate 1: Step b 2-Cyclobutylacetonitrile

To a solution of cyclobutylmethyl 4-methylbenzenesulfonate (108 g, 450mmol, Intermediate 1, step a) in DMSO (1000 mL) was added NaCN (33.1 g,675 mmol) and the mixture was stirred at 80° C. overnight. The mixturewas poured into water (2000 mL) and extracted with EtOAc (2×1000 mL).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness. The residue was distilledto give the title compound as a yellow oil.

Intermediate 1: Step c 1-Cyclobutylpropan-2-one

To a solution of 2-cyclobutylacetonitrile (1.00 g, 10.5 mmol,Intermediate 1, step b) in diethyl ether (10 mL) was addedmethylmagnesium iodide (10.5 mL, 3 M in diethylether) slowly at 0° C.under N₂ atmosphere. The mixture was stirred at rt overnight. Themixture was poured into ice (10 g) and 1 M aqueous HCl was added. Themixture was extracted with diethylether (2×15 mL). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness to give the title compound as a yellow oil,which was used in the next step without further purification.

Intermediate 1: Step d 1-Bromo-3-cyclobutylpropan-2-one

To a solution of 1-cyclobutylpropan-2-one (2.40 g, 21.4 mmol,Intermediate 1, step c) in MeOH (25 mL) was added Br₂ (0.88 mL, 17 mmol)dropwise at 0° C. and stirred at rt overnight. The mixture was extractedwith EtOAc (2×30 mL). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to drynessto give the title compound as a yellow oil.

Intermediate 1 Ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate

To a solution of 1-bromo-3-cyclobutylpropan-2-one (3.93 g, 20.7 mmol,Intermediate 1, step d) in EtOH (40 mL) was added ethyl2-amino-2-thioxoacetate (3.30 g, 24.8 mmol) and the mixture was stirredat 85° C. for 3 h. The resulting mixture was poured into water andextracted with EtOAc (2×50 mL). The residue was purified by FCC onsilica gel (PE/EtOAc=50/1) to give the title compound as a yellow oil.

Intermediate 1/1 Ethyl 4-(cyclopentylmethyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in step d 1-cyclopentylpropan-2-one in place of1-cyclobutylpropan-2-one.

Intermediate 1/2 Ethyl 4-(cyclohexylmethyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in step d 1-cyclohexylpropan-2-one in place of1-cyclobutylpropan-2-one.

Intermediate 1/3 Ethyl 4-isobutylthiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in step d 4-methylpentan-2-one in place of1-cyclobutylpropan-2-one.

Intermediate 1/4 Ethyl4-(2-methoxy-2-methylpropyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in step d 4-methoxy-4-methylpentan-2-one in placeof 1-cyclobutylpropan-2-one.

Intermediate 1/5 Ethyl4-((1-methoxycyclobutyl)methyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in step d 1-(1-methoxycyclobutyl)propan-2-one inplace of 1-cyclobutylpropan-2-one.

Intermediate 1/6 Ethyl 4-(4-fluorobenzyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in step d 1-(4-fluorophenyl)propan-2-one in placeof 1-cyclobutylpropan-2-one.

Intermediate 1/7 Ethyl 4-(hydroxymethyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in the final step 1-bromo-3-hydroxypropan-2-one inplace of 1-bromo-3-cyclobutylpropan-2-one.

Intermediate 1/8: Step a (3,3-Dimethylcyclobutyl)methyl4-methylbenzenesulfonate

A solution of borane in THF (1.0 M, 43.0 mL, 42.9 mmol) was added to anice-cooled solution of 3,3-dimethylcyclobutanecarboxylic acid (1.83 g,14.3 mmol) in THF (5 mL) and the reaction mixture was heated underreflux for 6 h, cooled, quenched by the dropwise addition of MeOH, andconcentrated under vacuum to afford a residue, which was dissolved inDCM (10 mL). Then TsCl (3.35 g, 18 mmol) and DMAP (360 mg, 3.0 mmol)were added and the mixture was stirred at rt overnight. Saturatedaqueous NaHCO₃ was added and the mixture was extracted with EtOAc (3×50mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated to drynessand the residue was purified by FCC on silica gel (PE/EtOAc=30:1) togive the title compound as a brown oil.

Intermediate 1/8: Step b 2-(3,3-Dimethylcyclobutyl)acetic acid

A suspension of (3,3-dimethylcyclobutyl)methyl 4-methylbenzenesulfonate(1.9 g, 7.1 mmol, Intermediate 1/8, step a), NaCN (0.69 g, 14 mmol) andTBAI (0.52 g, 1.4 mmol) in DMSO (20 mL) was heated at 80° C. overnight.The mixture was concentrated and the residue was diluted with H₂O andthen extracted with EtOAc. The aqueous layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated to dryness toafford an intermediate, which was treated with aqueous NaOH (8 N, 15mmol) and heated to reflux overnight. The mixture was cooled to rt, andpH adjusted to pH 3 by addition of HCl. The mixture was extracted withEtOAc (50 mL×3), dried and concentrated to dryness to afford the titlecompound as an amber oil.

Intermediate 1/8: Step c 1-(3,3-Dimethylcyclobutyl)propan-2-one

A suspension of 2-(3,3-dimethylcyclobutyl)acetic acid (320 mg, 2.25mmol, Intermediate 1/8, step b), N,O-dimethylhydroxylamine (280 mg, 4.6mmol), TEA (700 mg, 6.9 mmol) and HATU (1.31 g, 3.45 mmol) in MeCN (15mL) was stirred at rt for 2 h. Water (20 mL) was added and the aqueouslayer was extracted with EtOAc (20 mL×3). The combined organic layerswere washed with brine, concentrated to dryness, redissolved in THF (30mL) and cooled to −40° C. Methylmagnesium bromide (3 M in Et₂O, 2.5 mL,7.5 mmol) was added and the mixture stirred for 2 h. The mixture wasthen allowed to warm to rt, quenched with saturated aqueous NH₄Cl (30mL) and extracted with Et₂O (30 mL×3). The combined organic extractswere washed with brine and concentrated to dryness at 20° C. to affordthe title compound as a brown residue, which was used directly in thenext step.

Intermediate 1/8 Ethyl4-((3,3-dimethylcyclobutyl)methyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1, using in step d 1-(3,3-dimethylcyclobutyl)propan-2-one(Intermediate 1/8, step c) in place of 1-cyclobutylpropan-2-one.

Intermediate 1/9 Ethyl4-((3,3-difluorocyclobutyl)methyl)thiazole-2-carboxylate

The title compound was prepared as described for the synthesis ofIntermediate 1/8, using in step a 3,3-difluorocyclobutanecarboxylic acidin place of 3,3-dimethylcyclobutanecarboxylic acid.

Intermediate 1/10 Ethyl 4-(isopropoxymethyl)thiazole-2-carboxylate

To a solution of 1,3-dibromopropan-2-one (10.0 g, 46.3 mmol) inisopropanol (40 mL) was added ethyl 2-amino-2-thioxoacetate (6.8 g, 50mmol) and the mixture was stirred at 80° C. for 3 days, diluted withH₂O, and extracted with EtOAc (×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered, concentratedto dryness, and purified by FCC on silica gel (PE/EtOAc=3:1) to give thetitle compound as a brown oil.

Intermediate 2: Step a 4-(Cyclobutylmethyl)thiazole-2-carbohydrazide

To a mixture of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate (1.65g, 7.40 mmol, Intermediate 1) in EtOH (20 mL) hydrazine hydrate (4.2 mL)was added and the mixture was stirred at rt for 3 h. The mixture waspoured into ice-water (50 mL), and a precipitate was formed. Theprecipitate was collected through filtration and dried under vacuum togive a residue, which was recrystallized from DCM and PE to afford thetitle compound.

Intermediate 2: Step b Methyl4-(2-(4-(cyclobutylmethyl)thiazole-2-carbonyl)hydrazinyl)-2,2-dimethyl-4-oxobutanoate

To a solution of 4-methoxy-3,3-dimethyl-4-oxobutanoic acid (750 mg, 4.69mmol) in DCM (10 mL) was added SOCl₂ (0.9 mL, 9 mmol) followed by 3drops of DMF at 0° C. The mixture was allowed to warm to rt and stirredfor 4 h at this temperature. The solvent was removed under reducedpressure, and the residue was dissolved in freshly distilled DCM (2 mL).To a solution of 4-(cyclobutylmethyl)thiazole-2-carbohydrazide (1.10 g,4.86 mmol, Intermediate 2, step a) and TEA (1.0 mL, 7.2 mmol) in DCM (15mL) was added dropwise the above solution at 0° C. under nitrogenatmosphere. The resulting mixture was stirred at rt for 1 h. Thereaction was quenched with H₂O (10 mL) and extracted with DCM (3×30 mL).The combined organic layers were washed with H₂O (30 mL) and brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness.The residue was recrystallized from DCM and PE to give the titlecompound as a white solid.

Intermediate 2 Methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

To a mixture of methyl4-(2-(4-(cyclobutylmethyl)thiazole-2-carbonyl)hydrazinyl)-2,2-dimethyl-4-oxobutanoate(1.27 g, 3.60 mmol, Intermediate 2, step b) and pyridine (0.90 mL, 11mmol) in anhydrous DCM (15 mL) was added dropwise Tf₂O (1.25 mL, 7.2mmol) at −10° C. under nitrogen atmosphere. The mixture was stirred at−10° C. for 1 h, at 0° C. for 1 h, and then at rt for 1 h. The mixturewas concentrated to dryness and the residue was purified by FCC onsilica gel (PE/EtOAc=10/1) to give the title compound as a yellow oil.

An Alternative Synthesis of Intermediate 2 Intermediate 2: Step aa4-Bromothiazole-2-carbohydrazide

To a solution of ethyl 4-bromothiazole-2-carboxylate (900 g, 3.81 mol)in anhydrous EtOH (4.5 L) was added hydrazine hydrate (305 g, 80 wt % inwater, 7.62 mol) dropwise at 15-25° C. in one hour under an inertatmosphere of nitrogen, and the reaction solution was stirred at 15-25°C. for an additional 12 h. The crude reaction mixture was filtered andthe filter cake was washed with anhydrous EtOH (1 L). The filter cakewas collected and dried at room temperature to afford the title compoundas a light yellow solid.

Intermediate 2: Step bbMethyl-3-(5-(4-bromothiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

A flask was charged with EDC.HCl (1100 g, 5.73 mol,) and DMF (5 L). ThenHOBt (77.4 g, 0.57 mol), 4-bromothiazole-2-carbohydrazide (1272 g, 5.73mol, Intermediate 2, step aa) and DIPEA (2217 g, 17.18 mol) were addedsequentially. A solution of 4-methoxy-3,3-dimethyl-4-oxobutanoic acid(1100 g, 6.87 mol) in DMF (1.3 L) was added dropwise at 5-25° C. over 40minutes. The resulting solution was stirred at 25-37.5° C. and monitoredby HPLC. After the consumption of 4-bromothiazole-2-carbohydrazide wascomplete, DIPEA (1603 g, 11.46 mol) was added followed by dropwiseaddition of a solution of TsCl (1540 g, 7.45 mol) in DMF (1.5 L) at25-35° C. over 75 minutes. The resulting solution was stirred at 25-35°C. and monitored by HPLC. After completion of the reaction, the mixturewas poured into ice water (40 L) and then acidified to pH 3-4 by theaddition of concentrated aqueous HCl. The mixture was extracted withMTBE (2×20 L). The organic layers were combined and then washed withbrine (15 L) Anhydrous Na₂SO₄ and activated carbon (380 g) were added tothe organic layer, the suspension was stirred at room temperature for 12h. The crude product was filtered and the filter cake was washed withMTBE (2.5 L). The filtrate was concentrated under vacuum to afford thecrude solid product. To the crude solid was added isopropanol (6.5 L)and heptane (6.5 L) and the mixture was heated to 45-53° C. to form aclear solution. The solution was cooled down naturally to 20-25° C. Theresultant solids were isolated by filtration and were washed withisopropanol/heptane (1:1). To the solids were added MTBE (8.6 L) andheptane (1.73 L) and the suspension was heated to 48° C. to form a clearsolution. The solution was then cooled down naturally to 20-25° C. in 3h. The resultant solids were isolated by filtration to afford the titlecompound as a colorless solid.

Intermediate 2Methyl-3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2dimethylpropanoate

A flask was charged with magnesium turnings (49.5 g, 2.04 mol), THF (250mL) and 1,2-dibromoethane (4.7 g, 0.025 mol). The reaction suspensionwas cooled to 0-15° C. and a solution of cyclobutylmethyl bromide (300g, 2.01 mol) in THF (3 L) was added dropwise at 10-20° C. over 2.5 h.After addition, the suspension was stirred at 10-20° C. for 12 h. Afterthe reaction was complete, the content of the prepared Grignard reagentwas triturated using a dilute HCl solution. A flask was charged with theabove (cyclobutylmethyl) magnesium bromide in THF solution (1668 g, 11.9wt %, 1.16 mol) under an inert atmosphere of nitrogen. A solution ofZnCl₂ (78.8 g, 0.58 mol) in THF (800 mL) was then added dropwise at−5-0° C. over 50 minutes and the resulting suspension was warmed to20-25° C. over 2 h. A solution ofmethyl-3-(5-(4-bromothiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(200 g, 0.58 mol, Intermediate 2, step bb) in THF (400 mL) was the addedfollowed by Pd(dppf)Cl₂ (12.8 g, 17.5 mmol). The resulting solution wasstirred under nitrogen at 25-35° C. for 16 h and monitored by HPLC.After the reaction was complete, saturated aqueous NH₄Cl (1 L) was thenadded at 0-10° C. and the mixture was warmed to 20-25° C. The mixturewas then filtered and the filter cake was washed with MTBE (250 mL). Thefiltrate was collected and the organic layer was washed with asodium/potassium tartrate salt solution (15 wt. %). The insoluble solidswere removed by filtration, and the organic layer was washed with brine(1 L) and concentrated. To the crude product was added MTBE (1.9 L)under an inert atmosphere of nitrogen. An aqueous KMnO₄ solution (0.1 M,0.2 eq.) was then added dropwise at 0-10° C. over 30 minutes. Thereaction mixture was stirred at 0-10° C. for 8 h then was filteredthrough Celite®. The filter cake was washed with MTBE and the organiclayer was separated and concentrated under vacuum to afford the titlecompound as a light yellow oil.

Intermediate 2/1 Methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl4-(cyclohexylmethyl)thiazole-2-carboxylate (Intermediate 1/2) in placeof ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 2/2 Methyl3-(5-(4-isobutylthiazole-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl 4-isobutylthiazole-2-carboxylate(Intermediate 1/3) in place of ethyl4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 2/3 Methyl3-(5-(4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl4-(2-methoxy-2-methylpropyl)thiazol-2-carboxylate (Intermediate 1/4) inplace of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 2/4 Methyl3-(5-(4-(4-fluorobenzyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl4-(4-fluorobenzyl)thiazole-2-carboxylate (Intermediate 1/6) in place ofethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 2/5: Step a Ethyl4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carboxylate

To a solution of ethyl 4-(hydroxymethyl)thiazole-2-carboxylate (375 mg,2.00 mmol, Intermediate 1/7) in DCM (20 mL) was added DIPEA (516 mg,4.00 mmol) at 0° C. SEMCl (670 mg, 4.0 mmol) was added dropwise over aperiod of 10 min and the mixture was stirred overnight at rt. Themixture was quenched with water and extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine, dried, filtered andconcentrated to dryness. The residue was purified by FCC on silica gel(PE/ELOAc=20:1) to obtain the title compound.

Intermediate 2/5: Step b4-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carbohydrazide

A solution of ethyl4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carboxylate(3.17 g, 10.0 mmol, Intermediate 2/5, step a) and hydrazine monohydrate(2 mL) in EtOH (30 mL) was stirred at 50° C. for 4 h, concentrated todryness, and purified by FCC on silica gel (EtOAc) to give the titlecompound as a colorless oil.

Intermediate 2/5: Step c Methyl2,2-dimethyl-4-oxo-4-(2-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carbonyl)hydrazinyl)butanoate

A solution of4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carbohydrazide(2.7 g, 9.0 mmol, Intermediate 2/5, step b),4-methoxy-3,3-dimethyl-4-oxobutanoic acid (1.76 g, 11.0 mmol), HATU (4.2g, 11 mmol), and TEA (1.8 g, 18 mmol) in MeCN (40 mL) was stirred at rtfor 2 h, poured into water (40 mL), and extracted with EtOAc (50 mL×4).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, concentrated to dryness, and purified by FCC on silicagel (DCM/MeOH=10:1) to afford the title compound as a colorless oil.

Intermediate 2/5: Step d Methyl2,2-dimethyl-3-(5-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)propanoate

A mixture of methyl2,2-dimethyl-4-oxo-4-(2-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carbonyl)hydrazinyl)butanoate(1.6 g, 3.6 mmol, Intermediate 2/5, step c), TsCl (1.4 g, 7.2 mmol) andTEA (720 mg, 7.2 mmol) in DCM (30 mL) was stirred at rt overnight,poured into water (10 mL), and extracted with EtOAc (8 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, concentrated to dryness, and purified by FCC on silicagel (EtOAc/PE=1:5) to give the title compound as a colorless oil.

Intermediate 2/5 Methyl3-(5-(4-(hydroxymethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

A solution of methyl2,2-dimethyl-3-(5-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)propanoate(1.38 g, 3.24 mmol, Intermediate 2/5, step d) in HCl/dioxane (4 N, 40mL) was maintained at rt for 4 h and concentrated to dryness to affordthe title compound.

Intermediate 2/6 Methyl3-(5-(4-((3,3-dimethylcyclobutyl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl4-((3,3-dimethylcyclobutyl)methyl)thiazole-2-carboxylate (Intermediate1/8) in place of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 2/7 Methyl3-(5-(4-((3,3-difluorocyclobutyl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl4-((3,3-difluorocyclobutyl)methyl)thiazole-2-carboxylate (Intermediate1/9) in place of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 2/8: Step a 4-(Cyclohexylmethyl)thiazole-2-carbohydrazide

To a solution of ethyl 4-(cyclohexylmethyl)thiazole-2-carboxylate (2.0g, 7.9 mmol, Intermediate 1/2) in EtOH (10 mL) was added hydrazinehydrate (4.9 g, 98 mmol). The mixture was stirred at rt for 2 h. Theresulting solution was concentrated to dryness and the residue wasdissolved in EtOAc. The solution was washed with water twice, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to give thetitle compound as a pale yellow oil.

Intermediate 2/8: Step b1-(2-(4-(Cyclohexylmethyl)thiazole-2-carbonyl)hydrazinyl)-2-methyl-1-oxopropan-2-ylacetate

To a solution of 4-(cyclohexylmethyl)thiazole-2-carbohydrazide (1.7 g,7.1 mmol, Intermediate 2/8, step a) and TEA (2.2 g, 21 mmol) in DCM (10mL) was added 1-chloro-2-methyl-1-oxopropan-2-yl acetate (1.4 g, 8.5mmol) dropwise at 0° C., and the solution was stirred at rt for 5 h. Theresulting solution was washed with aqueous NaHCO₃, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness to give the title compoundas a brown solid.

Intermediate 2/82-(5-(4-(Cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-ylacetate

To a solution of1-(2-(4-(cyclohexylmethyl)thiazole-2-carbonyl)hydrazinyl)-2-methyl-1-oxopropan-2-ylacetate (2.5 g, 6.8 mmol, Intermediate 2/8, step b) and TEA (2.1 g, 20mmol) in DCM (20 mL) was added TsCl (2.0 g, 10 mmol) portionwise at 0°C., and the solution was stirred at rt for 2 h. The resulting solutionwas washed with water twice, dried over anhydrous Na₂SO₄, filtered,concentrated to dryness, and purified by FCC on silica gel(DCM/MeOH=50/1) to give the title compound as a colorless solid.

Intermediate 2/9 Methyl3-(5-(4-(cyclopentylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl4-(cyclopentylmethyl)thiazole-2-carboxylate (Intermediate 1/1) in placeof ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 2/10 Methyl3-(5-(4-(isopropoxymethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 2, using in step a ethyl4-(isopropoxymethyl)thiazole-2-carboxylate (Intermediate 1/10) in placeof ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 3: Step a 4-(Cyclobutylmethyl)thiazole-2-carboxamide

Ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate (0.84 g, 0.37 mmol,Intermediate 1) in a 7 M solution of NH₃ in MeOH (50 mL) was stirred at60° C. for 12 h. The mixture was concentrated to dryness to afford thetitle compound as a white solid.

Intermediate 3: Step b 4-(Cyclobutylmethyl)thiazole-2-carbonitrile

To a solution of 4-(cyclobutylmethyl)thiazole-2-carboxamide (0.72 g, 3.7mmol, Intermediate 3, step a) in DCM (20 mL) was added pyridine (146 mg,1.85 mmol) at 0° C. TFAA (1.55 g, 7.38 mmol) was added dropwise over aperiod of 10 min and the mixture was stirred for 1 h at thistemperature. Water was added and the mixture was extracted with EtOAc(3×50 mL), washed with brine, dried over anhydrous Na₂SO₄, andconcentrated to dryness. The residue was purified by preparative TLC(EtOAc) to afford the title compound.

Intermediate 3: Step c4-(Cyclobutylmethyl)-N′-hydroxythiazole-2-carboximidamide

A suspension of 4-(cyclobutylmethyl)thiazole-2-carbonitrile (650 mg,3.65 mmol, Intermediate 3, step b), NH₂OH.HCl (504 mg, 7.25 mmol) andNa₂CO₃ (2.32 g, 21.9 mmol) in a mixture of ethanol and water (20 mL, 5:1v/v) was refluxed for 3 h. The mixture was concentrated to dryness, andthe residue was diluted with water and extracted with with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to dryness to afford the title compound, whichwas used in the next step without further purification.

Intermediate 3 Methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

A mixture of 4-(cyclobutylmethyl)-N-hydroxythiazole-2-carboximidamide(698 mg, 3.30 mmol, Intermediate 3, step c), HATU (1.25 g, 3.29 mmol),DIPEA (1.65 mL, 9.49 mmol) and 4-methoxy-3,3-dimethyl-4-oxobutanoic acid(528 mg, 3.30 mmol) in DMF (10 mL) was stirred at rt for 1 h. Themixture was diluted with EtOAc, washed with water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated to dryness. The residue wasdissolved in DMF (5 mL) and heated at 120° C. for 12 h. Ice water wasadded and the mixture was extracted with EtOAc three times. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated to dryness and the residue waspurified by FCC on silica gel (PE/EtOAc, 5:1) to give the title compoundas a colorless solid.

Intermediate 3/1 Methyl3-(3-(4-(cyclohexylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 3, using in step a ethyl4-(cyclohexylmethyl)thiazole-2-carboxylate (Intermediate 1/2) in placeof ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 3/2 Methyl3-(3-(4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 3, using in step a ethyl4-(2-methoxy-2-methylpropyl)thiazole-2-carboxylate (Intermediate 1/4) inplace of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 3/3: Step a4-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carboxamide

A solution of ethyl4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carboxylate(3.17 g, 10.0 mmol, Intermediate 2/5, step a) in ammonia (7 N in MeOH,50 mL) was stirred at 60° C. for 12 h and concentrated under vacuum togive the title compound as a white solid.

Intermediate 3/3: Step b4-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carbonitrile

To a solution of4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carboxamide(2.88 g, 10.0 mmol, Intermediate 3/3, step a) in DCM (100 mL) was addedpyridine (1.46 g, 18.5 mmol) at 0° C. and then TFAA (4.19 g, 20.0 mmol)dropwise over 10 min. The mixture was stirred for 1 h at thistemperature, quenched with water, extracted with EtOAc (3×50 mL), washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness to give the title compound.

Intermediate 3/3: Step cN′-Hydroxy-4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carboximidamide

A suspension of4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carbonitrile(986 mg, 3.65 mmol, Intermediate 3/3, step b), NH₂OH.HCl (504 mg, 7.25mmol) and Na₂CO₃ (2.32 g, 21.9 mmol) in EtOH and water (20 mL, 5:1 v/v)was refluxed for 3 h, concentrated to dryness, redissolved in H₂O andextracted with EtOAc. The organic layer was washed with saturatedaqueous NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated todryness to afford the title compound.

Intermediate 3/3: Step d Methyl4-(((amino(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazol-2-yl)methylene)amino)oxy)-2,2-dimethyl-4-oxobutanoate

A mixture ofN′-hydroxy-4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazole-2-carboximidamide(1.0 g, 3.3 mmol, Intermediate 3/3, step c),4-methoxy-3,3-dimethyl-4-oxobutanoic acid (528 mg, 3.30 mmol), HATU(1.25 g, 3.29 mmol), and DIPEA (1.65 mL, 9.49 mmol) in DMF (20 mL) wasstirred at rt for 2 h, poured into water (120 mL) and extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, concentrated to dryness, and purified byFCC on silica gel (PE/EtOAc=1:1) to afford the title compound as ayellow oil.

Intermediate 3/3: Step e Methyl2,2-dimethyl-3-(3-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)propanoate

A solution of methyl4-(((amino(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazol-2-yl)methylene)amino)oxy)-2,2-dimethyl-4-oxobutanoate(1.0 g, 2.2 mmol, Intermediate 3/3, step d) in DMF (10 mL) was stirredat 120° C. for 12 h, poured into water (120 mL) and extracted with EtOAc(100 mL×3). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered, concentrated to dryness, and purifiedby FCC on silica gel (PE/EtOAc=1:1) to afford the title compound.

Intermediate 3/3 Methyl3-(3-(4-(hydroxymethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

Methyl2,2-dimethyl-3-(3-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)propanoate(350 mg, 0.82 mmol, Intermediate 3/3, step e) was treated withHCl/dioxane (11 mL, 4 M) for 1 h, quenched with NH₃/MeOH (7 mL, 7 M),poured into water (20 mL), and extracted with EtOAc (3×50 mL). Thecombined organic layers were concentrated to dryness to give the titlecompound.

Intermediate 3/4 Methyl3-(3-(4-((1-methoxycyclobutyl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 3, using in step a ethyl4-((1-methoxycyclobutyl)methyl)thiazole-2-carboxylate (Intermediate 1/5)in place of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate.

Intermediate 4: Step a 1-(Difluoromethyl)-2-fluoro-3-nitrobenzene

A solution of 2-fluoro-3-nitrobenzaldehyde (564 mg, 3.34 mmol) in DCM(20 mL) was cooled to −78° C. DAST (645 mg, 4.01 mmol) was addeddropwise and the mixture was stirred at rt for 1 h. The mixture waspoured into ice water, extracted with EtOAc (3×30 mL) and the combinedorganic layers were washed with brine and concentrated to dryness. Theresidue was purified by preparative TLC (PE/EtOAc=5:1) to give the titlecompound as a yellow solid.

Alternatively Intermediate 4, Step a was Prepared by the FollowingRoute:

2-Fluoro-3-nitrobenzaldehyde (1.0 g, 5.92 mmol) and anhydrous DCM (10mL) were added to a flask and the flask was cooled to −78° C. DAST (1.14g, 7.07 mmol) was then added dropwise, maintaining the temperature below−65° C. After addition, the reaction mixture was warmed slowly to 15-20°C. and stirred at this temperature for 4 h. The reaction mixture wasthen poured into ice water (10 mL), and the aqueous layer was extractedwith DCM (2×6 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃ (2×10 mL) and the aqueous wash was backextracted with DCM (2×5 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by FCC on silica gel (PE/EtOAc=10/1) to afford thetitle compound.

Intermediate 4: Step b 3-(Difluoromethyl)-2-fluoroaniline

Palladium on carbon (10 wt %, 80 mg) was added to a solution of1-(difluoromethyl)-2-fluoro-3-nitrobenzene (387 mg, 2.03 mmol,Intermediate 4, step a) in MeOH (20 mL). The mixture was stirred under ahydrogen atmosphere at rt overnight. The mixture was filtered through apad of Celite® and the filtrate was concentrated to dryness to give thetitle compound, which was used in the next step directly.

Alternatively Intermediate 4, Step b was Prepared by the FollowingRoute:

1-(Difluoromethyl)-2-fluoro-3-nitrobenzene (1 g, 5.92 mmol, Intermediate4, step a) and anhydrous MeOH (10 mL) were added to a high pressurereaction bottle. The reaction vessel was treated with 10 wt % Pd/C (200mg) in one portion under Ar. The resultant mixture was stirred at 10-20°C. under 30 psi of H₂ for 4 days. The reaction mixture was then filteredthrough Celite® and washed with MeOH (3×7.2 mL). The filtrate was driedover anhydrous Na₂SO₄, filtered and concentrated to dryness to affordthe title compound as a brown oil.

Intermediate 4: Step c 4-Bromo-3-(difluoromethyl)-2-fluoroaniline

A solution of 3-(difluoromethyl)-2-fluoroaniline (319 mg, 1.98 mmol,Intermediate 4, step b) in DMF (10 mL) was cooled to 0° C.N-Bromosuccinimide (480 mg, 2.38 mmol) was added portionwise and themixture was stirred at rt for 3 h. The mixture was poured into ice waterand extracted with EtOAc (3×30 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated to dryness and the residue was purified by FCCon silica gel (PE/EtOAc=5:1) to give the title compound as a whitesolid.

Alternatively Intermediate 4, Step c was Prepared by the FollowingRoute:

A solution of 3-(difluoromethyl)-2-fluoroaniline (5 g, 31.0 mmol,Intermediate 4, step b) in anhydrous DMF (50 mL) was cooled to −5° C.and treated with NBS (5.8 g, 32.6 mmol) in portions under N₂. Theresultant mixture was stirred for 1.5 h at −5° C. The reaction mixturewas poured into ice water, and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with water and brine,dried over Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by FCC on silica gel (1/100-1/5 EtOAc/PE) to afford the titlecompound.

Intermediate 4: Step d4-Bromo-3-(difluoromethyl)-2-fluorobenzene-1-sulfonyl chloride

Sodium nitrite (143 mg, 2.07 mmol) dissolved in water (5 mL) was addeddropwise to a −10° C. suspension of4-bromo-3-(difluoromethyl)-2-fluoroaniline (331 mg, 1.38 mmol,Intermediate 4, step c) in HCl/HOAc (15 mL, 10:5 v/v). The mixture wasstirred at −10° C. for 1 h and then poured into a complex of CuCl (0.1g, 0.1 mmol), HOAc and SO₂ (saturated) at 0° C., warmed to rt andstirred overnight. The mixture was poured into ice water, and theprecipitate was collected and dried to give the title compound as acolorless solid.

Alternatively Intermediate 4, Step d was Prepared by the FollowingRoute:

A solution of 4-bromo-3-(difluoromethyl)-2-fluoroaniline (1.0 g, 4.17mmol, Intermediate 4, step c) in acetic acid (7.5 mL) was treated withconcentrated HCl (5 mL, 60 mmol) in portions at 10-15° C. and cooled to−5° C. A solution of NaNO₂ (0.345 g, 5 mmol) in water (7.5 mL) was addeddropwise into the reaction vessel at −5-0° C. and stirred at thistemperature for 1 h. The reaction mixture was added to a precooledmixture of saturated solution of SO₂ in acetic acid (˜16 mL) andCuCl₂.H₂O (0.76 g, 5 mmol) in water (˜3 mL) at −5-0° C. The resultantmixture was warmed slowly to 0-15° C. and stirred for 1 h. The mixturewas poured into ice water (30 mL). The precipitate was filtered, thefiltrate was extracted with DCM (2×20 mL), and the precipitate wasdissolved with DCM (37.5 mL). The combined organic layers were washedwith saturated aqueous Na₂CO₃, washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by FCC onsilica gel (PE/DCM=10/1-5/1) to afford the title compound.

Intermediate 4(S)-4-Bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

A solution of 4-bromo-3-(difluoromethyl)-2-fluorobenzene-1-sulfonylchloride (246 mg, 0.761 mmol, Intermediate 4, step d),(S)-1,1,1-trifluorobutan-2-amine (106 mg, 0.835 mmol) and DMAP (0.1 g,0.8 mmol) in pyridine (20 mL) was stirred at 90° C. for 2 h. The mixturewas concentrated, water (20 mL) was added and the mixture was extractedwith EtOAc (4×20 mL). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness. The residue was purified by FCC on silica gel (PE/EtOAc=10:1)to afford the title compound as a colorless solid.

Alternatively Intermediate 4 was Prepared by the Following Route:

4-Bromo-3-(difluoromethyl)-2-fluorobenzene-1-sulfonyl chloride (0.5 g,1.5 mmol, Intermediate 4, step d) was added in one portion under N₂ to a−5° C. solution of (S)-1,1,1-trifluorobutan-2-amine (0.19 g, 1.5 mmol)and pyridine (1.5 mL). The resultant mixture was stirred for 1 h at −5°C., and then stirred at about 10° C. for 20 h before 1 M aqueous HCl (10mL) was added to the reaction mixture. The mixture was then extractedwith EtOAc (2×10 mL). The combined organic layers were washed with 1 Maqueous HCl and concentrated to dryness. The residue was purified by FCCon silica gel (PE/EtOAc=10/1) to give the title compound.

Intermediate 4/1(S)-4-Bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4 using in the final step (S)-1,1,1-trifluoropropan-2-aminein place of (S)-1,1,1-trifluorobutan-2-amine.

Intermediate 4/2(S)-4-Bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in step d 4-bromo-2,3-dichloroaniline in place of4-bromo-3-(difluoromethyl)-2-fluoroaniline and in the final step using(5)-1,1,1-trifluoropropan-2-amine in place of(5)-1,1,1-trifluorobutan-2-amine.

Intermediate 4/3(S)-4-Bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/2 using (5)-1,1,1-trifluorobutan-2-amine in place of(S)-1,1,1-trifluoropropan-2-amine.

Intermediate 4/44-Bromo-2,3-dichloro-N-(2,2,2-trifluoroethyl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/2 using 2,2,2-trifluoroethanamine in place of(S)-1,1,1-trifluoropropan-2-amine.

Intermediate 4/5 4-Bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/2 using 2-methylpropan-2-amine in place of(S)-1,1,1-trifluoropropan-2-amine.

Intermediate 4/6 4-Bromo-N-(tert-butyl)naphthalene-1-sulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in the final step 4-bromonaphthalene-1-sulfonylchloride in place of4-bromo-3-(difluoromethyl)-2-fluorobenzene-1-sulfonyl chloride and2-methylpropan-2-amine in place of (S)-1,1,1-trifluorobutan-2-amine.

Intermediate 4/7(S)-4-Bromo-N-(1,1,1-trifluoropropan-2-yl)naphthalene-1-sulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/6, using (5)-1,1,1-trifluoropropan-2-amine in place of2-methylpropan-2-amine.

Intermediate 4/8(S)-4-Bromo-N-(1,1,1-trifluorobutan-2-yl)naphthalene-1-sulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/6, using (5)-1,1,1-trifluorobutan-2-amine in place of2-methylpropan-2-amine.

Intermediate 4/9(S)-4-Bromo-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)-3-(trifluoromethyl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in step c 2-fluoro-3-(trifluoromethyl)aniline inplace of 3-(difluoromethyl)-2-fluoroaniline.

Intermediate 4/10(S)-4-Bromo-3-chloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in the final step4-bromo-3-chlorobenzene-1-sulfonyl chloride in place of4-bromo-3-(difluoromethyl)-2-fluorobenzene-1-sulfonyl chloride and(S)-1,1,1-trifluoropropan-2-amine in place of(S)-1,1,1-trifluorobutan-2-amine.

Intermediate 4/11(S)-4-Bromo-3-chloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/10, using (5)-1,1,1-trifluorobutan-2-amine in place of(S)-1,1,1-trifluoropropan-2-amine.

Intermediate 4/12(S)-4-Bromo-3-(trifluoromethyl)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in the final step4-bromo-3-(trifluoromethyl)benzene-1-sulfonyl chloride in place of4-bromo-3-(difluoromethyl)-2-fluorobenzene-1-sulfonyl chloride and(5)-1,1,1-trifluoropropan-2-amine in place of(S)-1,1,1-trifluorobutan-2-amine.

Intermediate 4/13(S)-4-Bromo-N-(1,1,1-trifluorobutan-2-yl)-3-(trifluoromethoxy)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in step c 3-(trifluoromethoxy)aniline in place of3-(difluoromethyl)-2-fluoroaniline.

Intermediate 4/14(S)-4-Bromo-3-(trifluoromethoxy)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/13 using (5)-1,1,1-trifluoropropan-2-amine in place of(S)-1,1,1-trifluorobutan-2-amine.

Intermediate 4/15(S)-4-Bromo-2-chloro-3-(difluoromethyl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in step a 2-chloro-3-nitrobenzaldehyde in place of2-fluoro-3-nitrobenzaldehyde.

Intermediate 4/16: Step a 5-Bromoisoquinoline-8-sulfonic acid

A solution of 5-bromoisoquinoline (2.07 g, 10.0 mmol) in fuming H₂SO₄(40 mL) was heated to 200° C. and stirred for 4 h. The mixture wascooled to rt and poured into ice. A precipitate was formed, which wascollected by filtration and dried under reduced pressure to give thetitle compound, which was used in the next step without furtherpurification.

Intermediate 4/16: Step b 5-Bromoisoquinoline-8-sulfonyl chloride

To a solution of 5-bromoisoquinoline-8-sulfonic acid (2.85 g, 9.89 mmol,Intermediate 4/16, step a) in POCl₃ (40 mL) was added PCl₅ (2.5 g, 12mmol) and the mixture was heated to 110° C. and stirred for 4 h. Themixture was concentrated to dryness to give the title compound as abrown solid, which was used in the next step without furtherpurification.

Intermediate 4/16(S)-5-Bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-8-sulfonamide

A solution of 5-bromoisoquinoline-8-sulfonyl chloride (1.5 g, 4.9 mmol,Intermediate 4/16, step b), (S)-1,1,1-trifluoropropan-2-amine (1.67 g,14.8 mmol) and DMAP (2.4 g, 10 mmol) in pyridine (50 mL) was heated to90° C. and stirred at this temperature overnight. The mixture wasconcentrated, water (50 mL) and EtOAc (50 mL) were added and the aqueouslayer was extracted with EtOAc twice. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness. The brown residue was purified by FCC on silicagel (PE/EtOAc=3:1) to give the title compound.

Intermediate 4/17(S)-8-Chloro-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-5-sulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/16, using in step a 8-chloroisoquinoline in place of5-bromoisoquinoline.

Intermediate 4/18(S)-5-Bromo-N-(1,1,1-trifluorobutan-2-yl)isoquinoline-8-sulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4/16, using in the final step(S)-1,1,1-trifluorobutan-2-amine in place of(S)-1,1,1-trifluoropropan-2-amine.

Intermediate 4/19: Step a 4-Bromoisoquinolin-1(2H)-one

A solution of isoquinolin-1(2H)-one (150 mg, 1.03 mmol) in DMF (5 mL)was treated with NBS (184 mg, 1.03 mmol). The mixture was stirred at rtfor 2 h and then poured into H₂O (15 mL). The formed precipitate wascollected by filtration, washed with water and dried by lyophilizationto give the title compound as a white solid.

Intermediate 4/19: Step b 4-Bromoisoquinoline-1(2H)-thione

A mixture of 4-bromoisoquinolin-1(2H)-one (200 mg, 0.90 mmol,Intermediate 4/19, step a) and P₂S₅ (220 mg, 1.0 mmol) in pyridine (1mL) was heated at 130° C. for 3 h. The mixture was cooled to rt andwater (3 mL) was added slowly. A precipitate was formed, which wascollected by filtration, washed with water and dried by lyophilizationto give the title compound as a yellow solid.

Intermediate 4/19(S)-4-Bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-1-sulfonamide

To a mixture of 4-bromoisoquinoline-1(2H)-thione (690 mg, 2.87 mmol,Intermediate 4/19, step b), DCM (15 mL), aqueous HCl (1 M, 15 mL) at −5°C. was added aqueous NaOC1 solution (6% w/w). The mixture was stirredfor 10 min and then loaded in a separation funnel. The DCM phase wasseparated and injected into a mixture of(S)-1,1,1-trifluoropropan-2-amine (325 mg, 2.87 mmol), DMAP (322 mg,2.87 mmol) and pyridine (15 mL). The resulting mixture was heated at 80°C. overnight. After cooling to rt, EtOAc (100 mL) was added and themixture was washed with aqueous HCl (1 M, 3×30 mL). The organic phasewas separated, dried over anhydrous Na₂SO₄, filtered and concentrated todryness to give a brown residue. The residue was purified by FCC onsilica gel (PE/EtOAc=10:1) to give the title compound as a white solid.

Intermediate 4/20(S)-4-Bromo-2-chloro-3-(difluoromethyl)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4 using in step a 2-chloro-3-nitrobenzaldehyde in place of2-fluoro-3-nitrobenzaldehyde and in the final step(S)-1,1,1-trifluoropropan-2-amine in place of(S)-1,1,1-trifluorobutan-2-amine.

Intermediate 4/21(S)-4-Bromo-2-(difluoromethyl)-3-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

The title compound was prepared as described for the synthesis ofIntermediate 4, using in step a 2-fluoro-6-nitrobenzaldehyde in place of2-fluoro-3-nitrobenzaldehyde.

Intermediate 4/22(R)-4-Bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

A solution of (R)-1,1,1-trifluorobutan-2-amine (982 mg, 7.73 mmol) inpyridine (3 mL) was cooled to −5° C. Then4-bromo-3-(difluoromethyl)-2-fluorobenzene-1-sulfonyl chloride (2.5 g,7.73 mmol, Intermediate 4, step d) was added and the resulting mixturewas stirred at −5° C. for 1 h then warmed to 10° C. for 20 h. 1 Naqueous HCl (20 mL) was then added and the mixture was extracted withEtOAc (2×20 mL). The combined organic layers were washed with 1 Naqueous HCl and concentrated to dryness. The residue was purified by FCCon silica gel (PE/EtOAc=10:1) to afford the title compound as a whitesolid.

Intermediate 54-(1-(4-Bromonaphthalen-1-yl)ethyl)-3,3-dimethylmorpholine

A solution of 1-(4-bromonaphthalen-1-yl)ethanone (2.49 g, 10.0 mmol),3,3-dimethylmorpholine (1.27 g, 11.0 mmol), and AcOH (5 drops) in DCM(30 mL) was stirred at rt for 30 min. Then NaBH(OAc)₃ (4.24 g, 20.0mmol) was added, and the suspension was stirred at rt overnight.Saturated aqueous NaHCO₃ solution was added to adjust the pH to 8, andthe two layers were separated. The organic layer was washed with waterand brine, dried over anhydrous Na₂SO₄, filtered, concentrated todryness and purified by FCC on silica gel (PE/EtOAc=2/1) to give thetitle compound as a pale yellow solid.

Intermediate 6: Step a1-(4-Bromo-2,3-dichlorophenyl)-2,2,2-trifluoroethanone

To a solution of 1-bromo-2,3-dichloro-4-iodobenzene (3.52 g, 10.0 mmol)in anhydrous THF (20 mL) was added n-BuLi (2.5 M in hexane, 4.4 mL, 11mmol) at −78° C. under nitrogen, and the solution was stirred at thistemperature for 30 min. The resulting solution was slowly added to asolution of 2,2,2-trifluoro-N-methoxy-N-methyl-acetamide (2.35 g, 14.8mmol) in anhydrous THF (25 mL) at −78° C., and the solution was stirredfor an additional 2 h. The solution was quenched with saturated aqueousNH₄Cl and extracted with EtOAc twice. The combined organic layers werewashed with water and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by FCC on silica gel(PE/EtOAc=100/1) to give the title compound as a pale yellow oil.

Alternate Synthesis of Intermediate 6: Step a

Isopropylmagnesium chloride lithium chloride complex (78.7 mL, 1.3 M inTHF, 102 mmol) was added dropwise to a −85-78° C. solution of1-bromo-2,3-dichloro-4-iodobenzene (30.0 g, 85.3 mmol) in THF (240 mL).Then 2,2,2-trifluoro-N-methoxy-N-methylacetamide (20.1 g, 128 mmol) wasadded one portion. The mixture was allowed to warm to 20-25° C. andstirred for 4 h. The reaction was quenched with saturated aqueous NH₄Cl(120 mL) and then diluted with EtOAc (150 mL). The layers wereseparated, and the aqueous layer was extracted with EtOAc (90 mL). Thecombined organic layers were washed with water (60 mL) and brine (60 mL)successively and concentrated under vacuum to give the title compound asa brown solid, which was used in the next step without furtherpurification.

Intermediate 62-(4-Bromo-2,3-dichlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

To a solution of 1-(4-bromo-2,3-dichlorophenyl)-2,2,2-trifluoroethanone(1.99 g, 6.18 mmol, Intermediate 6, step a) and TMSCF₃ (4.38 g, 30.9mmol) in anhydrous THF (30 mL) was added a solution of TBAF (2.45 g,9.27 mmol) in anhydrous THF (25 mL) at 0° C., and the solution wasstirred at rt overnight. The resulting solution was quenched with 1 Naqueous HCl, diluted with EtOAc, and the two layers were separated. Theorganic layer was washed with water and brine, dried over anhydrousNa₂SO₄, filtered, concentrated to dryness and purified by FCC on silicagel (PE/EtOAc=5/1) to give the title compound as a yellow oil.

Alternate Synthesis of Intermediate 6

A solution of TBAF (14.3 g, 46.6 mmol) in THF (40 mL) was added dropwiseto a stirring −15-10° C. solution of1-(4-bromo-2,3-dichlorophenyl)-2,2,2-trifluoroethanone (10.0 g, 31.1mmol, Intermediate 6, step a) and TMSCF₃ (22.1 g, 155 mmol) in THF (10mL). Then the reaction was quenched with 2 N aqueous HCl (78 mL),diluted with EtOAc (50 mL), and the layers were separated. The organiclayer was washed with water (40 mL) and brine (40 mL) successively andconcentrated. The residue was dissolved with heptane (50 mL), and DABCO(1.7 g, 15.2 mmol) was added one portion. The mixture was stirredovernight, filtered, and the cake was washed with heptane (10 mL×2). Thecake was dissolved with EtOAc (100 mL), washed with 1 N aqueous HCl (30mL×3), and concentrated to dryness to give the title compound as a brownliquid.

Intermediate 7: Step a 4-Bromo-2,3-dichlorobenzyl methanesulfonate

To a solution of 4-bromo-2,3-dichloro-benzaldehyde (2.00 g, 7.88 mmol)in MeOH (15 mL) was added NaBH₄ (756 mg, 20.0 mmol) slowly, and thesuspension was stirred at rt for 1 h. The resulting suspension wasquenched with saturated aqueous NH₄Cl, concentrated under reducedpressure and diluted with EtOAc and water. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness to give a residue. To this residue was added DCM (20 mL), TEA(2.02 g, 20.0 mmol) and MsC1 (2.30 g, 20.1 mmol), and the mixture wasstirred for 1 h. The resulting solution was quenched with water, and theorganic layer was dried over anhydrous Na₂SO₄, filtered, concentratedunder reduced pressure and purified by preparative TLC (PE/EtOAc=100/1)to give the title compound as a colorless solid.

Intermediate 7 4-(4-Bromo-2,3-dichlorobenzyl)-3,3-dimethylmorpholine

A suspension of 4-bromo-2,3-dichlorobenzyl methanesulfonate (735 mg,2.20 mmol, Intermediate 7, step a), 3,3-dimethyl-morpholine (512 mg,4.45 mmol) and K₂CO₃ (828 mg, 6.00 mmol) in MeCN (10 mL) was refluxedovernight. The suspension was cooled to rt, filtered, concentrated todryness and purified by FCC on silica gel (PE/EtOAc=5/1) to give thetitle compound as a colorless solid.

Intermediate 7/14-((4-Bromonaphthalen-1-yl)methyl)-3,3-dimethylmorpholine

The title compound was prepared as described for the synthesis ofIntermediate 7, using in step a 4-bromo-1-naphthaldehyde in place of4-bromo-2,3-dichloro-benzaldehyde.

Intermediate 8: Step a1-(3-Bromo-5-(tert-butyl)phenyl)-2,2,2-trifluoroethanone

To a solution of 1,3-dibromo-5-(tert-butyl)benzene (5.84 g, 20.0 mmol)in anhydrous THF (60 mL) was added n-BuLi (2.5 M in THF, 10 mL, 25 mmol)at −78° C. under nitrogen and the solution was stirred for 40 min. Then2,2,2-trifluoro-N-methoxy-N-methyl-acetamide (3.93 g, 25.0 mmol) wasadded slowly at this temperature, and the solution was warmed to rt andstirred overnight, quenched with saturated NH₄Cl and extracted withEtOAc twice. The combined organic layers were washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness. The residue was purified by FCC on silica gel (PE) followed bypreparative HPLC to give the title compound as a yellow oil.

Intermediate 82-(3-Bromo-5-(tert-butyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

To a solution of1-(3-bromo-5-(tert-butyl)phenyl)-2,2,2-trifluoroethanone (3.77 g, 12.2mmol, Intermediate 8, step a) and TMSCF₃ (2.33 mL, 15.0 mmol) in dry DME(50 mL) was added anhydrous CsF (60.8 mg, 0.40 mmol) at rt undernitrogen, and the mixture was stirred for 3 h at rt. Then an additionalportion of TMSCF₃ (1.00 mL, 6.44 mmol) was added, and the mixturestirred for 2 h, diluted with 2 N aqueous HCl, stirred for 18 h at rtand extracted with EtOAc twice. The combined organic layers were washedwith water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by FCC on silica gel(PE/EtOAc=10/1) followed by preparative HPLC to give the title compoundas a colorless oil.

Intermediate 9: Step a1,3-Dibromo-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

To a stirred mixture of methyltriphenylphosphonium bromide (3.34 g, 9.35mmol) in anhydrous THF (10 mL) was added t-BuOK (1.04 g, 9.35 mmol)under N₂ atmosphere at −40° C., and the mixture was stirred for 30 minat this temperature. Then a solution of1-(3,5-dibromophenyl)-2,2,2-trifluoroethanone (2.99 g, 9.01 mmol) inanhydrous THF (30 mL) was added dropwise. The solution was stirred at rtovernight, quenched with aqueous NH₄Cl at 0° C. and extracted withEtOAc. The organic layer was concentrated to dryness and the residue waspurified by FCC on silica gel (PE) to give the title compound as acolorless solid.

Intermediate 9: Step b1,3-Dibromo-5-(1-(trifluoromethyl)cyclopropyl)benzene

To a suspension of 1,3-dibromo-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(1.80 g, 5.46 mmol; Intermediate 9, step a) and Pd(OAc)₂ (300 mg, 1.3mmol) in anhydrous THF (10 mL) at 0° C. was added a solution of CH₂N₂ inEt₂O (2 M, 20 mL, 40 mmol) dropwise and the mixture was stirred at rtovernight, filtered and concentrated to dryness. This procedure wasrepeated four times and the crude product was purified by FCC on silicagel (PE) to give the title compound as a colorless oil.

Intermediate 9: Step c Methyl3-bromo-5-(1-(trifluoromethyl)cyclopropyl)benzoate

To a solution of 1,3-dibromo-5-(1-(trifluoromethyl)cyclopropyl)benzene(3.44 g, 10.0 mmol, Intermediate 9, step b) in THF (40 mL) was addedn-BuLi (2.5 M, 4.40 mL, 11.0 mmol) at −78° C. and the mixture wasstirred at this temperature for 1 h. Methyl chloroformate (1.04 g, 11.0mmol) was added slowly. The mixture was allowed to reach rt in 2 h,quenched with saturated aqueous NH₄Cl and extracted with EtOAc threetimes. The combined organic layers were washed with brine, dried overanhydrous MgSO₄, filtered and concentrated to dryness. The residue waspurified by FCC on silica gel (PE/EtOAc=50/1) to give the title compoundas a colorless oil.

Intermediate 9: Step d 3-Bromo-5-(1-(trifluoromethyl)cyclopropyl)benzoicacid

To a solution of methyl3-bromo-5-(1-(trifluoromethyl)cyclopropyl)benzoate (1.0 g, 3.1 mmol,Intermediate 9, step c) in a mixture of THF/water (12 mL, 5:1 v/v) wasadded LiOH.H₂O (1.26 g, 30.0 mmol) and the solution was stirredovernight at rt, partially concentrated and the pH was adjusted to pH=4with 1 N aqueous HCl. The precipitate formed was collected by filtrationand dried in vacuo to give the title compound as a colorless solid.

Intermediate 9(S)-3-Bromo-5-(1-(trifluoromethyl)cyclopropyl)-N-(1,1,1-trifluoropropan-2-yl)benzamide

A solution of (S)-1,1,1-trifluoropropan-2-amine hydrochloride (449 mg,3.00 mmol), 3-bromo-5-(1-(trifluoromethyl)cyclopropyl)benzoic acid (880mg, 2.85 mmol, Intermediate 9, step d), DIPEA (775 mg, 6.00 mmol) andHATU (1.14 g, 3.00 mmol) in DMF (10 mL) was stirred overnight at rt. Themixture was concentrated to dryness and the residue was purified by FCCon silica gel (PE/EtOAc=10/1) to give the title compound as a colorlesssolid.

Intermediate 10(S)-3-Bromo-5-(1-methylcyclopropyl)-N-(1,1,1-trifluoropropan-2-yl)benzamide

The title compound was prepared as described for the synthesis ofIntermediate 9, using in the final step3-bromo-5-(1-methylcyclopropyl)benzoic acid (prepared as described inWO2013/079223, Preparative Example P33c) in place of3-bromo-5-(1-(trifluoromethyl)cyclopropyl)benzoic acid.

Intermediate 11: Step a 1-Bromo-2-(difluoromethyl)-4-iodobenzene

Diethylaminosulfur trifluoride (77.8 g, 482 mmol) was added to asolution of 2-bromo-5-iodobenzaldehyde (100 g, 322 mmol) and DCM (1 L)at 0° C. The resultant mixture was stirred at room temperature for 2 hbefore quenching with ice/water (1 L) and extracting with DCM (800mL×3). The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to dryness to give the crudeproduct, which was purified by FCC on silica gel (PE/EtOAc=50:1) toafford the title compound.

Intermediate 11: Step b1-(4-Bromo-3-(difluoromethyl)phenyl)-2,2,2-trifluoroethanone

Isopropylmagnesium chloride lithium chloride complex (194 mL, 1.3 M inTHF, 252 mmol) was added dropwise to a solution of1-bromo-2-(difluoromethyl)-4-iodobenzene (70.0 g, 210 mmol, Intermediate11, step a) and anhydrous THF (200 mL) at −78° C. The resultant mixturewas stirred at −78° C. for 30 minutes and then treated with2,2,2-trifluoro-N-methoxy-N-methylacetamide (49.5 g, 315 mmol). Theresultant mixture was stirred at −78° C. under N₂ for 1 h before it wasquenched with saturated aqueous NH₄Cl (600 mL) solution and extractedwith EtOAc (800 mL×3). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to give thecrude product, which was purified by FCC on silica gel (PE/EtOAc=10:1 to4:1) to afford the title compound.

Intermediate 112-(4-Bromo-3-(difluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Tetrabutylammonium fluoride (470 mL, 1 M in THF, 470 mmol) was addeddropwise to a solution of1-(4-bromo-3-(difluoromethyl)phenyl)-2,2,2-trifluoroethanone (95.0 g,313 mmol, Intermediate 11, step b), TMSCF₃ (223 g, 1.6 mol), andanhydrous THF (100 mL) at −15° C. The resultant mixture was stirred at−15-10° C. for 30 minutes and then was allowed to warm to rt over 2 hbefore it was quenched with 2 N aqueous HCl (400 mL) and extracted withEtOAc (800 mL×3). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to give thecrude product, which was purified by FCC on silica gel (PE/EtOAc=100:1to 20:1) to afford the title compound.

Intermediate 12: Step a Ethyl 2,2-dimethyl-3-(thiazol-2-yl)propanoate

To a solution of ethyl 3-iodo-2,2-dimethylpropanoate (2.5 g, 10 mmol,Intermediate 14, step a) in THF (50 mL) was added dropwise n-BuLi (4.8mL, 12 mmol, 2.5 M in THF) at −78° C. under an Ar atmosphere and themixture was stirred for 1 h at that temperature. A 0.5 M solution ofZnCl₂ in THF (24 mL, 12 mmol) was added, and the mixture was stirred for30 min at −78° C. The solution was allowed to warm to rt and stirred for1 h. 2-Bromothiazole (1.6 g, 10 mmol), Pd₂(dba)₃ (0.45 g, 0.49 mmol) anddppf (0.54 g, 0.98 mmol) were added, and the mixture was stirred for 20h at 60° C. After cooling, the mixture was treated with water (50 mL)and extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated to dryness. Theresidue was purified by FCC on silica gel (PE/EtOAc=15:1) to give thetitle compound as a colorless liquid.

Intermediate 12: Step b Ethyl3-(5-bromothiazol-2-yl)-2,2-dimethylpropanoate

To a solution of ethyl 2,2-dimethyl-3-(thiazol-2-yl)propanoate (1.1 g,5.2 mmol, Intermediate 12, step a) in CH₃CN (30 mL) was added NBS (1.1g, 6.2 mmol). The mixture was stirred 3 h at reflux temperature, cooledto rt and quenched with aqueous Na₂SO₃ (50 mL). The mixture wasextracted with EtOAc (3×50 mL) and the combined organic layers wereconcentrated to dryness. The residue was purified by FCC on silica gel(PE/EtOAc=30:1) to give the title compound as a colorless liquid.

Intermediate 12 Ethyl2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)propanoate

To a solution of ethyl 3-(5-bromothiazol-2-yl)-2,2-dimethylpropanoate(616 mg, 2.12 mmol, Intermediate 12, step b), bis(pinacolato)diboron(646 mg, 2.54 mmol) and KOAc (519 mg, 5.30 mmol) in 1,4-dioxane (10 mL)was added Pd(dppf)Cl₂ (50 mg, 68 μmol) and the solution was stirred at90° C. overnight. The mixture was allowed to cool to rt and partitionedbetween EtOAc and water. The organic layer was washed with water andbrine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by FCC on silica gel (PE/EA=10:1) to give the titlecompound as a colorless solid.

Intermediate 13 4-(Cyclobutylmethyl)thiazole

A mixture of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate (300 mg,1.3 mmol, Intermediate 1) and KOH (230 mg, 3.9 mmol) in ethanol (10 mL)and water (3 mL) was stirred for 4 h at rt. The pH was adjusted to pH 3with 1 M aqueous HCl and the mixture was extracted with EtOAc (3×50 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was treated with HCl/dioxane (15mL) at rt for 1 h. Water was added and the mixture was extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by preparative TLC (PE/EtOAc=50:1) to afford the titlecompound.

Intermediate 14: Step a Ethyl 3-iodo-2,2-dimethylpropanoate

To a solution of ethyl isobutyrate (15 g, 130 mmol) in THF at −78° C.was added slowly LDA (2 M in hexane, 71 mL, 142 mmol). The mixture wasstirred at −78° C. for 1 h, then CH₂I₂ (24.9 g, 92.9 mmol) was added.The mixture was warmed to rt overnight, poured into saturated aqueousNH₄Cl (100 mL) and extracted with EtOAc. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated to dryness.The residue was purified by fractional distillation to afford the titlecompound as a colorless liquid.

Intermediate 14: Step b Ethyl3-(6-bromopyridin-2-yl)-2,2-dimethylpropanoate

A suspension of Zn—Cu couple (690 mg, 10.5 mmol) in toluene/DMA (6 mL,11:1 v/v) was purged with Ar for 15 min. Ethyl3-iodo-2,2-dimethylpropanoate (340 mg, 1.35 mmol, Intermediate 14, stepa) was added to the suspension, and the resulting mixture was heated at110° C. for 3 h. The mixture was cooled to 70° C., and2,6-dibromopyridine (320 mg, 1.35 mmol) and Pd(PPh₃)₄ (47 mg, 0.040mmol) were added. The mixture was stirred at 80° C. for 16 h, allowed tocool, filtered and concentrated to dryness. The residue was purified bypreparative TLC (PE/EtOAc=8:1) to give the title compound.

Intermediate 14 Ethyl3-(6-(4-(cyclobutylmethyl)thiazol-2-yl)pyridin-2-yl)-2,2-dimethylpropanoate

To a solution of 4-(cyclobutylmethyl)thiazole (180 mg, 1.17 mmol,Intermediate 13) in THF (8 mL) at −78° C. was added n-BuLi (1.6 M inhexane, 1.5 mL, 2.4 mmol). The mixture was stirred at −78° C. for 2 hand then a solution of ZnCl₂ in THF (1 M, 5.9 mL, 5.9 mmol) was added.The mixture was stirred at −78° C. for 1.5 h and then allowed to warm tort. Ethyl 3-(6-bromopyridin-2-yl)-2,2-dimethylpropanoate (337 mg, 1.17mmol, Intermediate 14, step b) and Pd(PPh₃)₄ (135 mg, 117 μmol) wereadded and the mixture was stirred at 60° C. overnight. The mixture wasallowed to cool to rt, diluted with EtOAc (50 mL) and washed withsaturated aqueous NH₄Cl (3×15 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to give aresidue, which was purified by preparative TLC (PE/EtOAc=15/1) to givethe title compound.

Intermediate 15: Step a Ethyl3-(6-chloropyrimidin-4-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 14, step b, using 4,6-dichloropyrimidine in place of2,6-dibromopyridine.

Intermediate 15 Ethyl3-(6-(4-(Cyclobutylmethyl)thiazol-2-yl)pyrimidin-4-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofIntermediate 14, using in the final step ethyl3-(6-chloropyrimidin-4-yl)-2,2-dimethylpropanoate (Intermediate 15, stepa) in place of ethyl 3-(6-bromopyridin-2-yl)-2,2-dimethylpropanoate.

Intermediate 16: Step a (S)-tert-Butyl4,4-difluoro-2-methylpyrrolidine-1-carboxylate

Under a nitrogen atmosphere, DAST (0.60 mL, 4.4 mmol) was added to asolution of (S)-tert-butyl 2-methyl-4-oxopyrrolidine-1-carboxylate (420mg, 2.10 mmol) in DCM (5.0 mL) under ice cooling and the resultantmixture was stirred for 16 h at rt and quenched with saturated aqueousNaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered,concentrated to dryness, and purified by FCC on silica gel(PE/EtOAc=70/1) to give the title compound as a yellow oil.

Intermediate 16 (S)-4,4-Difluoro-2-methylpyrrolidine hydrochloride

To a solution of (S)-tert-butyl4,4-difluoro-2-methylpyrrolidine-1-carboxylate (250 mg, 1.13 mmol,Intermediate 16, step a) in 1,4-dioxane (2 mL) was added a solution ofHCl in 1,4-dioxane (4 M, 5.0 mL) at 0° C. The mixture was stirred at rtfor 1 h and concentrated to dryness to give the title compound as a redsolid.

Intermediate 17 (S)-3,3-Difluoro-2-methylpyrrolidine hydrochloride

The title compound was prepared as described for the synthesis ofIntermediate 16 using in step a (S)-tert-butyl2-methyl-3-oxopyrrolidine-1-carboxylate in place of (S)-tert-butyl2-methyl-4-oxopyrrolidine-1-carboxylate.

Intermediate 18N-(tert-Butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-sulfonamide

A mixture of 4-bromo-N-(tert-butyl)naphthalene-1-sulfonamide (55.0 g,161 mmol, Intermediate 4/6), bis(pinacolato)diboron (42.0 g, 165 mmol),K₂CO₃ (92.0 g, 667 mmol) and Pd(dppf)Cl₂ (5.0 g, 6.1 mmol) in1,4-dioxane (600 mL) was stirred under nitrogen at 90° C. overnight. Theresulting solution was allowed to cool to rt, concentrated to drynessand the residue was purified by FCC on silica gel (PE/EtOAc===10/1) togive the title compound as a pale yellow solid.

Example 1 Step a2-(5-(5-(4-(N-(tert-Butyl)sulfamoyl)-3-(trifluoromethyl)phenyl)-4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-ylacetate

A mixture of2-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-ylacetate (150 mg, 0.43 mmol, Intermediate 2/8),4-bromo-N-(tert-butyl)-2-(trifluoromethyl)benzenesulfonamide (155 mg,0.430 mmol, prepared as described for Intermediate 4, using2-(trifluoromethyl)aniline in place of3-(difluoromethyl)-2-fluoroaniline in step c), KOAc (126 mg, 1.28 mmol),PPh₃ (113 mg, 0.431 mmol), Pd(OAc)₂ (50 mg, 0.22 mmol) and DMF (5 mL)was purged with N₂ and heated at 120° C. overnight. The resultingsolution was allowed to cool to rt and diluted with EtOAc. The solutionwas washed with water three times, dried over anhydrous Na₂SO₄,filtered, concentrated to dryness, and purified by FCC on silica gel(DCM/MeOH=100/1) to give the title compound as a colorless solid.

Example 1N-(tert-Butyl)-4-(4-(cyclohexylmethyl)-2-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)thiazol-5-yl)-2-(trifluoromethyl)benzenesulfonamide

A solution of2-(5-(5-(4-(N-(tert-butyl)sulfamoyl)-3-(trifluoromethyl)phenyl)-4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-ylacetate (250 mg, 0.398 mmol, Example 1, step a) and LiOH.H₂O (52 mg, 1.2mmol) in a mixture of MeOH (10 mL) and water (2 mL) was stirred at rtfor 1 h. The resulting mixture was concentrated to dryness, and theresulting residue was dissolved in EtOAc. The solution was washed withwater twice, dried over anhydrous Na₂SO₄, filtered, concentrated todryness, and purified by preparative HPLC to give the title compound asa colorless solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.40 (d, J=8.0 Hz,1H), 7.93 (s, 1H), 7.78-7.75 (m, 1H), 4.74 (s, 1H), 2.75 (d, J=8.0 Hz,2H), 2.64 (s, 1H), 1.89-1.88 (m, 1H), 1.82 (s, 6H), 1.66-1.64 (m, 4H),1.30 (s, 9H), 1.29-1.12 (m, 4H), 0.93-0.88 (m, 2H). MS (APCI): m/z 585.2[M−H]⁻.

Example 1/1N-(tert-Butyl)-4-(4-(cyclohexylmethyl)-2-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)thiazol-5-yl)naphthalene-1-sulfonamide

The title compound was prepared as described for the synthesis ofExample 1 using in step a4-bromo-N-(tert-butyl)naphthalene-1-sulfonamide (Intermediate 4/6) inplace of 4-bromo-N-(tert-butyl)-2-(trifluoromethyl)benzenesulfonamide.¹H NMR (300 MHz, CDCl₃): δ ppm 8.71 (d, J=8.1 Hz, 1H), 8.37 (d, J=8.1Hz, 1H), 7.77-7.70 (m, 2H), 7.62-7.56 (m, 2H), 4.69 (s, 1H), 2.72 (s,1H), 2.45 (br s, 2H), 1.82 (s, 6H), 1.54-1.50 (m, 6H), 1.25 (s, 9H),0.95-1.20 (m, 3H), 0.61-0.69 (m, 2H). MS (ESI): m/z 569.2 [M+H]⁺.

Example 2 Step a 5-Bromo-4-(cyclohexylmethyl)thiazole-2-carbohydrazide

To a solution of ethyl5-bromo-4-(cyclohexylmethyl)thiazole-2-carboxylate (1.00 g, 3.01 mmol,prepared as described in WO2013/178362, Example 6, step 3) in EtOH (15mL) was added aqueous 85% hydrazine hydrate (1.24 g, 21.1 mmol), and thesolution was stirred at rt for 1 h. The resulting solution wasconcentrated to dryness and purified by FCC on silica gel (EtOAc/PE=1/3)to give the title compound as a colorless solid.

Example 2 Step b

2-(5-Bromo-4-(cyclohexylmethyl)thiazol-2-yl)-5-methyl-1,3,4-oxadiazole

A solution of 5-bromo-4-(cyclohexylmethyl)thiazole-2-carbohydrazide (250mg, 0.786 mmol, Example 2, step a) in Ac₂O (5 mL) was heated at 45° C.for 1 h under nitrogen. The resulting solution was cooled to rt, pouredinto saturated aqueous NaHCO₃ and extracted with EtOAc twice. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness. Pyridine (154 mg, 1.94mmol) and DCM (25 mL) were then added, followed by Tf₂O (460 mg, 1.63mmol) under N₂ at −10° C., and the solution was stirred at −10° C. for 1h, at 0° C. for 1 h, and at rt for 30 min. The resulting solution wasconcentrated to dryness and purified by FCC on silica gel(EtOAc/PE=1/10) to give the title compound as a colorless solid.

Example 2N-(tert-Butyl)-4-(4-(cyclohexylmethyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)thiazol-5-yl)naphthalene-1-sulfonamide

A solution of2-(5-bromo-4-(cyclohexylmethyl)thiazol-2-yl)-5-methyl-1,3,4-oxadiazole(100 mg, 0.292 mmol, Example 2, step b),N-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-sulfonamide(142 mg, 0.366 mmol, Intermediate 18), Pd(dppf)Cl₂ (24 mg, 0.029 mmol)and Na₂CO₃ (2 M in water, 1.6 mL, 3.2 mmol) in DME (5 mL) was purgedwith nitrogen for 15 min and heated at reflux temperature overnight.After cooling to rt, the resulting solution was diluted with EtOAc andwater. The layers were separated, and the aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered, concentrated to dryness, and purifiedby FCC on silica gel (EtOAc/PE=1/1) to give the title compound as anoff-white solid. ¹H NMR (400 MHz, CD₃OD): δ ppm 8.84 (d, J=8.0 Hz, 1H),8.35 (d, J=8.0 Hz, 1H), 7.80-7.64 (m, 4H), 2.69 (s, 3H), 2.50-2.45 (m,2H), 1.70-1.66 (m, 1H), 1.52-1.50 (m, 5H), 1.10 (s, 9H), 1.07-0.97 (m,3H), 0.72-0.67 (m, 2H). MS (ESI): m/z 525.2 [M+H]⁺.

Example 3 Step a Methyl3-(5-(5-(4-(N-(tert-butyl)sulfamoyl)-2,3-dichlorophenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

A mixture of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(200 mg, 600 μmol, Intermediate 2),4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide (323 mg, 0.900mmol, Intermediate 4/5), Pd(OAc)₂ (80 mg, 0.4 mmol), KOAc (156 mg, 1.50mmol) and PPh₃ (60 mg, 0.2 mmol) in DMF (15 mL) was stirred at 95° C.for 24 h under nitrogen atmosphere. After cooling to rt, the mixture wasdiluted with EtOAc (75 mL), washed with water (3×50 mL) and brine (50mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness.The residue was purified by FCC on silica gel (PE/EtOAc=6/1) to give thetitle compound as a yellow oil.

Example 33-(5-(5-(4-(N-(tert-Butyl)sulfamoyl)-2,3-dichlorophenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(5-(5-(4-(N-(tert-butyl)sulfamoyl)-2,3-dichlorophenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(178 mg, 0.289 mmol, Example 3, step a) in a mixture of THF, MeOH andH₂O (15 mL, 1:1:1 v/v/v) was added LiOH.H₂O (122 mg, 2.89 mmol). Theresultant mixture was stirred at rt overnight. The pH was adjusted to pH2 with 1 M aqueous HCl and the precipitate was collected by filtration.The precipitate was washed with diethyl ether and dried to give thetitle compound as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm12.57 (br s, 1H). 8.13 (d, J=8.3 Hz, 1H), 8.06 (s, 1H), 7.75 (d, J=8.3Hz, 1H), 3.21 (s, 2H), 2.71-2.55 (m, 3H), 1.94-1.45 (m, 6H), 1.27 (s,6H), 1.17 (s, 9H). MS (ESI): m/z 601.1 [M+H]⁺.

Example 3/13-(5-(5-(4-(N-(tert-Butyl)sulfamoyl)naphthalen-1-yl)-4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand 4-bromo-N-(tert-butyl)naphthalene-1-sulfonamide (Intermediate 4/6)in place of 4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹HNMR (300 MHz, CDCl₃): δ ppm 8.72 (d, J=8.1 Hz, 1H), 8.37 (d, J=8.1 Hz,1H), 8.25 (br s, 1H), 7.77-7.69 (m, 2H), 7.61-7.55 (m, 2H), 5.14 (s,1H), 3.30 (s, 2H), 2.44 (m, 2H), 1.76 (m, 1H), 1.60-1.47 (m, 4H), 1.44(s, 6H), 1.22 (s, 9H), 1.15-0.80 (m, 4H), 0.71-0.54 (m, 2H). MS (ESI):m/z 611.3 [M+H]⁺.

Example 3/23-(5-(5-(4-(N-(tert-Butyl)sulfamoyl)-2,3-dichlorophenyl)-4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid (Intermediate 2/1) instead of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate.¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.53 (br s, 1H), 8.11 (d, J=8.3 Hz,1H), 8.03 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 3.20 (s, 2H), 1.69-1.55 (m,2H), 1.53-1.46 (m, 6H), 1.26 (s, 6H), 1.14-0.99 (m, 12H), 0.78-0.71 (m,2H). MS (ESI): m/z 629.1 [M+H]⁺.

Example 3/3(S)-3-(5-(4-(Cyclobutylmethyl)-5-(4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)naphthalene-1-sulfonamide(Intermediate 4/7) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (300 MHz,DMSO-d₆): δ ppm 12.58 (br s, 1H), 9.05 (br s, 1H), 8.75 (d, J=8.7 Hz,1H), 8.30 (d, J=7.5 Hz, 1H), 7.86-7.69 (m, 4H), 4.12-4.01 (m, 1H), 3.24(s, 2H), 2.63-2.54 (m, 2H), 1.87-1.13 (m, 13H), 1.05 (d, J=6.9 Hz, 3H).MS (ESI): m/z 632.2 [M+H]⁺.

Example 3/4(S)-3-(5-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/3) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (300 MHz,CDCl₃): δ ppm 8.08 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 5.33 (d,J=10.2 Hz, 1H), 3.94-3.88 (m, 1H), 2.74-2.72 (m, 3H), 3.28 (s, 2H),1.97-1.51 (m, 7H), 1.44 (s, 6H), 1.28-1.25 (m, 2H), 1.11 (t, J=7.5 Hz,3H). MS (ESI): m/z 655.1 [M+H]⁺.

Example 3/53-(5-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(2,2,2-trifluoroethyl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a4-bromo-2,3-dichloro-N-(2,2,2-trifluoroethyl)benzenesulfonamide(Intermediate 4/4) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (300 MHz,CDCl₃): δ ppm 8.11 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 5.65 (brs, 1H), 3.85-3.79 (m, 2H), 3.28 (s, 2H), 2.75-2.70 (m, 3H), 2.01-1.53(m, 6H), 1.43 (s, 6H). MS (ESI): m/z 627.0 [M+H]⁺.

Example 3/63-(5-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-((3,3-dimethylmorpholino)methyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a4-(4-bromo-2,3-dichlorobenzyl)-3,3-dimethylmorpholine (Intermediate 7)in place of 4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹HNMR (300 MHz, CDCl₃): δ ppm 7.69 (d, J=8.1 Hz, 1H), 7.29-7.26 (m, 1H),3.76-3.72 (m, 4H), 3.44 (s, 2H), 3.27 (s, 2H), 2.74-2.73 (m, 3H),2.56-2.50 (m, 2H), 1.98-1.52 (m, 6H), 1.41 (s, 6H), 1.14 (s, 6H). MS(ESI): m/z 593.2 [M+H]⁺.

Example 3/73-(5-(4-(Cyclobutylmethyl)-5-(4-((3,3-dimethylmorpholino)methyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a4-((4-bromonaphthalen-1-yl)methyl)-3,3-dimethylmorpholine (Intermediate7/1) in place of 4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide.¹H NMR (300 MHz, CDCl₃): δ ppm 8.38 (d, J=9.0 Hz, 1H), 7.71-7.44 (m,5H), 4.08 (s, 2H), 3.70-3.67 (m, 2H), 3.48 (s, 2H), 3.29 (s, 2H),2.70-2.68 (m, 3H), 2.53-2.50 (m, 2H), 1.91-1.43 (m, 6H), 1.40 (s, 6H),1.23 (s, 6H). MS (ESI): m/z 575.2 [M+H]⁺.

Example 3/8 Step a Methyl3-(5-(4-(cyclobutylmethyl)-5-(4-(1-(3,3-dimethylmorpholino)ethyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

The title compound was prepared as described for the synthesis ofExample 3, using in step a4-(1-(4-bromonaphthalen-1-yl)ethyl)-3,3-dimethylmorpholine (Intermediate5) in place of 4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide.

Example 3/8a and 3/8b Step b Methyl3-(5-(4-(cyclobutylmethyl)-5-(4-(1-(3,3-dimethylmorpholino)ethyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

Chiral HPLC separation (Chiralpak OD-H column, hexane: EtOH=80/20) ofmethyl3-(5-(4-(cyclobutylmethyl)-5-(4-(1-(3,3-dimethylmorpholino)ethyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Example 3/8, step a) afforded Example 3/8a, step b (faster elutingenantiomer with a retention time of 7.060 min) and Example 3/8b, step b(slower eluting enantiomer with a retention time of 8.037 min).

Example 3/8a and 3/8b3-(5-(4-(Cyclobutylmethyl)-5-(4-(1-(3,3-dimethylmorpholino)ethyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

Example 3/8a was prepared as described for the synthesis of Example 3,using in the final step methyl3-(5-(4-(cyclobutylmethyl)-5-(4-(1-(3,3-dimethylmorpholino)ethyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Example 3/8a, step b) instead of methyl3-(5-(5-(4-(N-(tert-butyl)sulfamoyl)-2,3-dichlorophenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate.¹H NMR (300 MHz, CDCl₃): δ ppm 8.30 (d, J=8.4 Hz, 1H), 7.81 (d, J=7.2Hz, 1H), 7.69-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.50-7.44 (m, 2H),5.02-4.99 (m, 1H), 3.94-3.90 (m, 1H), 3.73-3.68 (m, 1H), 3.39-3.37 (m,2H), 3.29 (s, 2H), 3.18-3.09 (m, 1H), 2.74-2.67 (m, 4H), 1.90-1.86 (m,2H), 1.69-1.58 (m, 2H), 1.50 (d, J=6.9 Hz, 3H), 1.46-1.43 (m, 2H), 1.40(s, 6H), 1.25 (s, 3H), 0.89 (s, 3H). MS (ESI): m/z 589.3 [M+H]⁺. Example3/8b was prepared as described for the synthesis of Example 3, using inthe final step methyl3-(5-(4-(cyclobutylmethyl)-5-(4-(1-(3,3-dimethylmorpholino)ethyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Example 3/8b, step b) instead of methyl3-(5-(5-(4-(N-(tert-butyl)sulfamoyl)-2,3-dichlorophenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate.¹H NMR (300 MHz, CDCl₃) δ ppm 8.30 (d, J=8.4 Hz, 1H), 7.81 (d, J=7.2 Hz,1H), 7.69-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.50-7.44 (m, 2H), 5.02-4.99(m, 1H), 3.94-3.90 (m, 1H), 3.73-3.68 (m, 1H), 3.39-3.37 (m, 2H), 3.29(s, 2H), 3.18-3.09 (m, 1H), 2.74-2.67 (m, 4H), 1.90-1.86 (m, 2H),1.69-1.58 (m, 2H), 1.50 (d, J=6.9 Hz, 3H), 1.46-1.43 (m, 2H), 1.40 (s,6H), 1.25 (s, 3H), 0.89 (s, 3H). MS (ESI): m/z 589.3 [M+H]⁺.

Example 3/9(S)-3-(5-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.11 (d, J=8.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 5.51 (d,J=10.0 Hz, 1H), 4.13-4.07 (m, 1H), 3.29 (s, 2H), 2.75-2.63 (m, 3H),1.99-1.93 (m, 2H), 1.79-1.69 (m, 2H), 1.56-1.43 (m, 11H). MS (ESI): m/z641.0 [M+H]⁺.

Example 3/10(S)-3-(5-(5-(2-Chloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(S)-4-bromo-3-chloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/10) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.03 (s, 1H), 7.86-7.84 (m, 1H), 7.55 (d, J=8.0 Hz, 1H),4.13-4.06 (m, 1H), 3.27 (s, 2H), 2.76-2.62 (m, 3H), 1.96-1.90 (m, 2H),1.78-1.64 (m, 2H), 1.51-1.39 (m, 11H). MS (ESI): m/z 607.2 [M+H]⁺.

Example 3/11(S)-3-(5-(4-(Cyclobutylmethyl)-5-(2-(trifluoromethoxy)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-4-bromo-3-(trifluoromethoxy)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/14) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.94-7.90 (m, 2H), 7.67 (d, J=8.0 Hz, 1H), 5.42 (d, J=9.2Hz, 1H), 4.13-4.09 (m, 1H), 3.29 (s, 2H), 2.81-2.68 (m, 3H), 1.99-1.93(m, 2H), 1.81-1.67 (m, 2H), 1.56-1.51 (m, 2H), 1.44-1.42 (m, 9H). MS(ESI): m/z 657.1 [M+H]⁺.

Example 3/12(S)-3-(5-(4-(Cyclobutylmethyl)-5-(2-(trifluoromethyl)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(S)-4-bromo-3-(trifluoromethyl)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/12) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.30 (s, 1H), 8.15-8.12 (m, 1H), 7.60 (d, J=8.4 Hz, 1H),5.35 (d, J=9.2 Hz, 1H), 4.16-4.10 (m, 1H), 3.28 (s, 2H), 2.72-2.64 (m,3H), 1.96-1.67 (m, 4H), 1.54-1.52 (m, 2H), 1.46-1.31 (m, 9H). MS (ESI):m/z 641.1 [M+H]⁺.

Example 3/13(S)-3-(5-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-4-isobutylthiazole-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-isobutylthiazole-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/2) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 12.59 (br s, 1H), 9.24 (d, J=8.8 Hz, 1H), 8.11 (d, J=8.2Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 4.21-4.15 (m, 1H), 3.22 (s, 2H),2.49-2.46 (m, 2H), 2.03-1.96 (m, 1H), 1.28-1.27 (m, 9H), 0.77 (d, J=6.4Hz, 6H). MS (ESI): m/z 629.0 [M+H]⁺.

Example 3/14(S)-3-(5-(4-Isobutyl-5-(2-(trifluoromethoxy)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-isobutylthiazole-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/2) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-3-(trifluoromethoxy)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/14) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.93-7.89 (m, 2H), 7.66 (d, J=8.4 Hz, 1H), 5.27 (d, J=9.2Hz, 1H), 4.15-4.06 (m, 1H), 3.29 (s, 2H), 2.57 (d, J=7.2 Hz, 1H),2.17-2.11 (m, 1H), 1.44-1.42 (m, 9H), 0.80 (d, J=6.8 Hz, 6H). MS (ESI):m/z 645.2 [M+H]⁺.

Example 3/15(S)-3-(5-(4-(Cyclohexylmethyl)-5-(1-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-4-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-1-sulfonamide(Intermediate 4/19) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 9.02-9.00 (m, 1H), 8.49 (s, 1H), 7.87-7.83 (m, 2H),7.80-7.77 (m, 1H), 5.58 (d, J=8.8 Hz, 1H), 4.28-4.23 (m, 1H), 3.31 (s,2H), 2.50-2.48 (m, 2H), 1.84-1.78 (m, 1H), 1.61 (d, J=7.2 Hz, 3H),1.57-1.54 (m, 5H), 1.48 (s, 6H), 1.18-0.97 (m, 3H), 0.72-0.64 (m, 2H).MS (ESI): m/z 651.9 [M+H]⁺.

Example 3/16(S)-3-(5-(4-(Cyclobutylmethyl)-5-(8-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-5-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-5-bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-8-sulfonamide(Intermediate 4/16) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 12.59 (br s, 1H), 10.15 (br s, 1H), 9.33 (d, J=9.2 Hz,1H), 8.76-8.75 (m, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.08 (d, J=7.4 Hz, 1H),7.72 (s, 1H), 4.20-4.17 (m, 1H), 3.25 (s, 2H), 2.69-2.58 (m, 3H),1.84-1.79 (m, 2H), 1.68-1.52 (m, 2H), 1.38-1.34 (m, 8H), 1.10 (d, J=6.8Hz, 3H). MS (ESI): m/z 624.1 [M+H]⁺.

Example 3/17(S)-3-(5-(4-(Cyclobutylmethyl)-5-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-8-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-8-chloro-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-5-sulfonamide(Intermediate 4/17) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 12.59 (br s, 1H), 9.25-9.20 (m, 2H), 8.83 (d, J=6.0 Hz,1H), 8.57 (dd, J=0.8, 6.4 Hz, 1H), 8.51-8.49 (m, 1H), 7.95 (d, J=7.6 Hz,1H), 4.20-4.15 (m, 1H), 3.25 (s, 2H), 2.66-2.56 (m, 3H), 1.86-1.82 (m,2H), 1.55-1.52 (m, 2H), 1.41-1.30 (m, 8H), 1.07 (d, J=6.8 Hz, 3H). MS(ESI): m/z 624.2 [M+H]⁺.

Example 3/18(S)-3-(5-(4-(Cyclobutylmethyl)-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)-2-(trifluoromethoxy)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-4-bromo-N-(1,1,1-trifluorobutan-2-yl)-3-(trifluoromethoxy)benzenesulfonamide(Intermediate 4/13) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.94-7.90 (m, 2H), 7.66 (d, J=6.8 Hz, 1H), 5.37 (br s,1H), 3.93-3.90 (m, 1H), 3.28 (s, 2H), 2.80 (d, J=5.6 Hz, 2H), 2.71-2.68(m, 1H), 1.96-1.92 (m, 3H), 1.78-1.71 (m, 2H), 1.56-1.50 (m, 3H), 1.43(s, 6H), 1.07 (t, J=6.0 Hz, 3H). MS (ESI): m/z 671.2 [M+H]⁺.

Example 3/19(S)-3-(5-(5-(2-Chloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(S)-4-bromo-3-chloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/11) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 8.80 (br s, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.93 (dd,J=1.2, 6.4 Hz, 1H), 7.84 (d, J=6.4 Hz, 1H), 4.08-4.05 (m, 1H), 3.21 (s,2H), 2.69 (d, J=5.6 Hz, 2H), 2.58-2.55 (m, 1H), 1.93-1.87 (m, 2H),1.75-1.61 (m, 3H), 1.49-1.40 (m, 3H), 1.27 (s, 6H), 0.63 (t, J=6.0 Hz,3H). MS (ESI): m/z 621.1 [M+H]⁺.

Example 3/20(S)-3-(5-(4-(Cyclohexylmethyl)-5-(4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)naphthalene-1-sulfonamide(Intermediate 4/7) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.67 (d, J=6.8 Hz, 1H), 8.34 (d, J=6.0 Hz, 1H), 7.79-7.73(m, 2H), 7.64-7.57 (m, 2H), 5.11 (d, J=7.6 Hz, 1H), 4.06-4.01 (m, 1H),3.30 (s, 2H), 2.44 (m, 2H), 1.74-1.73 (m, 1H), 1.52-1.48 (m, 5H), 1.43(s, 6H), 1.39-1.30 (m, 3H), 1.12-0.93 (m, 3H), 0.65-0.58 (m, 2H). MS(ESI): m/z 650.9 [M+H]⁺.

Example 3/21(S)-3-(5-(4-(Cyclohexylmethyl)-5-(2-(trifluoromethoxy)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-3-(trifluoromethoxy)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/14) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.93-7.88 (m, 2H), 7.65 (d, J=6.8 Hz, 1H), 5.19-5.16 (m,1H), 4.12-4.08 (m, 1H), 3.29 (s, 2H), 2.57 (d, J=6.8 Hz, 2H), 1.81-1.78(m, 1H), 1.60-1.54 (m, 5H), 1.44-1.42 (m, 9H), 1.17-1.03 (m, 3H),0.78-0.72 (m, 2H). MS (ESI): m/z 684.8 [M+H]⁺.

Example 3/22(S)-3-(5-(4-(Cyclohexylmethyl)-5-(8-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-5-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (5)-5-bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-8-sulfonamide(Intermediate 4/16) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 10.12 (s, 1H), 9.34 (d, J=8.8 Hz, 1H), 8.73 (d, J=6.0 Hz,1H), 8.37 (d, J=7.6 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.73 (d, J=6.0 Hz,1H), 4.22-4.16 (m, 1H), 3.25 (s, 2H), 2.44-2.38 (m, 2H), 1.65-1.61 (m,1H), 1.48-1.43 (m, 5H), 1.31 (s, 6H), 1.11-0.93 (m, 6H), 0.64-0.57 (m,2H). MS (ESI): m/z 652.2 [M+H]⁺.

Example 3/23(S)-3-(5-(4-(Cyclohexylmethyl)-5-(8-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)isoquinolin-5-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (5)-5-bromo-N-(1,1,1-trifluorobutan-2-yl)isoquinoline-8-sulfonamide(Intermediate 4/18) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 10.38 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 8.43 (d, J=7.6 Hz,1H), 7.90-7.86 (m, 2H), 7.72 (d, J=6.0 Hz, 1H), 3.84-3.82 (m, 1H), 3.32(s, 2H), 2.43-2.42 (m, 2H), 1.87-1.46 (m, 14H), 1.14-0.94 (m, 6H),0.55-0.65 (m, 2H). MS (ESI): m/z 666.3 [M+H]⁺.

Example 3/24(S)-3-(5-(4-(Cyclohexylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/1) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 12.57 (br s, 1H), 9.34 (d, J=8.8 Hz, 1H), 8.10 (t, J=7.6Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.04 (t, J=51.6 Hz, 1H), 4.22-4.17 (m,1H), 3.23 (s, 2H), 2.46-2.42 (m, 2H), 1.67-1.52 (m, 6H), 1.28 (s, 6H),1.24-1.00 (m, 6H), 0.76-0.71 (m, 2H). MS (ESI): m/z 668.8 [M+H]⁺.

Example 3/25(S)-3-(5-(5-(3-Chloro-2-(difluoromethyl)-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-4-bromo-2-chloro-3-(difluoromethyl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/15) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.27 (d, J=6.4 Hz, 1H), 7.43 (d, J=6.8 Hz, 1H), 6.97 (t,J=42.2 Hz, 1H), 5.38 (d, J=8.0 Hz, 1H), 3.91-3.86 (m, 1H), 3.29 (s, 2H),2.80-2.65 (m, 3H), 1.95-1.91 (m, 3H), 1.81-1.43 (m, 11H), 1.12 (t, J=6.0Hz, 3H). MS (ESI): m/z 670.8 [M+H]⁺.

Example 3/26(S)-3-(5-(4-(Cyclohexylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclohexylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/1) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.06 (t, J=7.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.67 (t,J=52.4 Hz, 1H), 5.29 (d, J=9.6 Hz, 1H), 4.01-3.88 (m, 1H), 3.29 (s, 2H),2.47 (br s, 2H), 1.97-1.90 (m, 1H), 1.81-1.76 (m, 1H), 1.66-1.52 (m,6H), 1.44 (s, 6H), 1.21-1.04 (m, 6H), 0.78-0.71 (m, 2H). MS (ESI): m/z683.3 [M+H]⁺.

Example 3/27(S)-3-(5-(4-(2-Methoxy-2-methylpropyl)-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/3) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (S)-4-bromo-N-(1,1,1-trifluorobutan-2-yl)naphthalene-1-sulfonamide(Intermediate 4/8) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.68 (d, J=6.4 Hz, 1H), 8.33 (d, J=6.0 Hz, 1H), 7.72-7.81(m, 2H), 7.61-7.64 (m, 2H), 5.13 (d, J=8.0 Hz, 1H), 3.85-3.87 (m, 1H),3.30 (s, 2H), 2.67-3.01 (m, 5H), 1.81-1.87 (m, 1H), 1.47-1.57 (m, 1H),1.43 (s, 6H), 0.96-1.04 (m, 9H). MS (ESI): m/z 655.2 [M+H]⁺.

Example 3/28(S)-3-(5-(4-(2-Methoxy-2-methylpropyl)-5-(4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/3) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)naphthalene-1-sulfonamide(Intermediate 4/7) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.66 (d, J=8.8 Hz, 1H), 8.34 (d, J=7.6 Hz, 1H), 7.82-7.73(m, 2H), 7.64-7.61 (m, 2H), 5.03 (d, J=9.6 Hz, 1H), 4.05-4.00 (m, 1H),3.30 (s, 2H), 2.87-2.81 (m, 5H), 1.44 (s, 6H), 1.32 (d, J=7.2 Hz, 3H),1.05 (s, 6H). MS (ESI): 641.3 [M+H]⁺.

Example 3/29(S)-3-(5-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-4-((3,3-dimethylcyclobutyl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-((3,3-dimethylcyclobutyl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/6) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.11 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 4.11-4.06(m, 1H), 3.26 (s, 2H), 2.72 (d, J=7.2 Hz, 2H), 2.58-2.52 (m, 1H),1.78-1.73 (m, 2H), 1.45 (d, J=7.2 Hz, 3H), 1.35-1.25 (m, 8H), 1.03 (s,3H), 0.91 (s, 3H). MS (ESI): m/z 669.1 [M+H]⁺.

Example 3/30(S)-3-(5-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluorocyclobutyl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-((3,3-difluorocyclobutyl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/7) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/3) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.10 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 5.41 (d,J=10.0 Hz, 1H), 3.89-3.85 (m, 1H), 3.29 (s, 2H), 2.81 (d, J=7.2 Hz, 2H),2.67-2.56 (m, 3H), 2.22-2.12 (m, 2H), 1.94-1.89 (m, 1H), 1.66-1.58 (m,1H), 1.44 (s, 6H), 1.11 (t, J=7.2 Hz, 3H). MS (ESI): m/z 691.0 [M+H]⁺.

Example 3/31(S)-3-(5-(4-((3,3-Difluorocyclobutyl)methyl)-5-(4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-((3,3-difluorocyclobutyl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/7) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)naphthalene-1-sulfonamide(Intermediate 4/7) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.69 (d, J=8.4 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H), 7.79-7.58(m, 4H), 5.14 (d, J=9.6 Hz, 1H), 4.06-4.00 (m, 1H), 3.31 (s, 2H),2.74-2.50 (m, 5H), 2.07-2.00 (m, 2H), 1.45 (s, 6H), 1.33 (d, J=7.2 Hz,3H). MS (ESI): m/z 659.1 [M+H]⁺.

Example 3/32(S)-3-(5-(5-(2-(Difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(4-fluorobenzyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(4-fluorobenzyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/4) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.99 (t, J=7.8 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.00-6.86(m, 4H), 6.66 (t, J=52.8 Hz, 1H), 5.37 (d, J=10.4 Hz, 1H), 3.99-3.90 (m,3H), 3.28 (s, 2H), 1.97-1.91 (m, 1H), 1.67-1.52 (m, 1H), 1.43 (s, 6H),1.13 (t, J=7.2 Hz, 3H). MS (ESI): m/z 695.2 [M+H]⁺.

Example 3/33(S)-3-(5-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-4-(4-fluorobenzyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(4-fluorobenzyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/4) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 12.57 (br s, 1H), 9.22 (d, J=9.2 Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.10-7.01 (m, 4H), 4.19-4.15 (m, 1H),4.02 (s, 2H), 3.21 (s, 2H), 1.27-1.25 (m, 9H). MS (ESI): m/z 681.0[M+H]⁺.

Example 3/343-(5-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a2-(4-bromo-2,3-dichlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 6) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (300 MHz,CD₃OD): δ ppm 8.04-7.91 (m, 1H), 7.60-7.56 (m, 1H), 3.27-3.25 (m, 2H),2.87-2.68 (m, 3H), 2.01-1.95 (m, 2H), 1.84-1.57 (m, 4H), 1.37 (s, 6H).MS (ESI): m/z 632.0 [M+H]⁺.

Example 3/35(S)-3-(5-(4-(Cyclobutylmethyl)-5-(3-(1-methylcyclopropyl)-5-((1,1,1-trifluoropropan-2-yl)carbamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-3-bromo-5-(1-methylcyclopropyl)-N-(1,1,1-trifluoropropan-2-yl)benzamide(Intermediate 10) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (300 MHz,CDCl₃): δ ppm 7.78 (s, 1H), 7.67 (s, 1H), 7.39 (s, 1H), 7.03 (d, J=7.2Hz, 1H), 5.01-4.95 (m, 1H), 3.22 (s, 2H), 2.81-2.79 (m, 2H), 2.73-2.64(m, 1H), 1.98-1.95 (m, 2H), 1.77-1.57 (m, 4H), 1.49-1.45 (m, 6H),1.34-1.33 (m, 6H), 0.93-0.90 (m, 2H), 0.86-0.83 (m, 2H). MS (ESI): m/z591.1 [M+H]⁺.

Example 3/363-(5-(5-(3-(tert-Butyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a2-(3-bromo-5-(tert-butyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 8) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (CDCl₃,300 MHz): δ ppm 7.80 (m, 1H), 7.66-7.65 (m, 1H), 7.55 (s, 1H), 3.27-3.25(d, J=4.8 Hz, 2H), 2.95-2.75 (m, 3H), 2.03-1.98 (m, 2H), 1.77-1.65 (m,5H), 1.41 (s, 6H), 1.38 (s, 9H). MS (ESI): m/z 620.2 [M+H]⁺.

Example 3/37(S)-3-(5-(4-(Cyclobutylmethyl)-5-(3-(1-(trifluoromethyl)cyclopropyl)-5-((1,1,1-trifluoropropan-2-yl)carbamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a(5)-3-bromo-5-(1-(trifluoromethyl)cyclopropyl)-N-(1,1,1-trifluoropropan-2-yl)benzamide(Intermediate 9) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (CDCl₃,300 MHz): δ ppm 7.99 (s, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 7.15 (d, J=9.9Hz, 1H), 5.05-4.92 (m, 1H), 3.21 (s, 2H), 2.82-2.80 (m, 2H), 2.78-2.65(m, 1H), 1.98-1.95 (m, 2H), 1.77-1.54 (m, 4H), 1.50-1.42 (m, 5H), 1.32(s, 6H), 1.11 (s, 2H). MS (ESI): m/z 645.2 [M+H]⁺.

Example 3/38(S)-3-(5-(4-(Cyclopentylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclopentylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/9) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.08-8.04 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.67 (t, J=52.4Hz, 1H), 3.94-3.89 (m, 1H), 3.27 (s, 2H), 2.61 (br s, 2H), 2.28-2.20 (m,1H), 1.95-1.90 (m, 1H), 1.66-1.58 (m, 3H), 1.52-1.45 (m, 4H), 1.40 (s,6H), 1.11 (t, J=7.6 Hz, 3H), 0.99-0.95 (m, 2H). MS (ESI): m/z 669.0[M+H]⁺.

Example 3/39(S)-3-(5-(4-(Isopropoxymethyl)-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(isopropoxymethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/10) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (S)-4-bromo-N-(1,1,1-trifluorobutan-2-yl)naphthalene-1-sulfonamide(Intermediate 4/8) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 12.61 (s, 1H), 9.00 (d, J=8.8 Hz, 1H), 8.80 (d, J=8.4Hz, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.88-7.69 (m, 4H), 4.35-4.29 (m, 2H),3.92-3.88 (m, 1H), 3.37-3.34 (m, 2H), 3.25 (s, 1H), 1.65-1.40 (m, 2H),1.29 (s, 6H), 0.80 (d, J=6.4 Hz, 6H), 0.59 (t, J=7.2 Hz, 3H). MS (ESI):m/z 640.9 [M+H]⁺.

Example 3/40(S)-3-(5-(5-(3-Chloro-2-(difluoromethyl)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-4-(cyclopentylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclopentylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/9) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-Bromo-2-chloro-3-(difluoromethyl)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/20) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (500 MHz,DMSO-d₆): δ ppm 12.58 (br s, 1H), 9.24 (d, J=7.0 Hz, 1H), 8.27 (d, J=8.0Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.22 (t, J=52.0 Hz, 1H), 4.17 (s, 1H),3.23 (s, 2H), 2.64-2.18 (m, 3H), 1.61 (br s, 2H), 1.42-1.41 (m, 4H),1.28-1.25 (m, 9H), 1.25-1.00 (m, 2H). MS (ESI): m/z 671.0 [M+H]⁺.

Example 3/41(S)-3-(5-(4-(Cyclopentylmethyl)-5-(3-(difluoromethyl)-2-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclopentylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/9) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2-(difluoromethyl)-3-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/21) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (500 MHz,DMSO-d₆): δ ppm 12.58 (br s, 1H), 9.32 (br s, 1H), 7.97-7.92 (m, 2H),7.77 (t, J=51.0 Hz, 1H), 3.95-3.93 (m, 1H), 3.22 (s, 2H), 2.68 (d, J=7.0Hz, 2H), 2.20-2.15 (m, 1H), 1.70-1.42 (m, 8H), 1.28 (m, 6H), 0.99-0.94(m, 2H), 0.77 (t, J=7.5 Hz, 3H). MS (ESI): m/z 669.2 [M+H]⁺.

Example 3/423-(5-(5-(2-(Difluoromethyl)-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(4-fluorobenzyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(4-fluorobenzyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(Intermediate 2/4) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand2-(4-bromo-3-(difluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 11) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (500 MHz,DMSO-d₆): δ ppm 12.57 (m, 1H), 9.20 (m, 1H), 8.04 (m, 1H), 7.92 (d,J=8.5 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.08-6.87 (m, 5H), 3.98 (s, 2H),3.21 (m, 2H), 1.27 (m, 6H). MS (ESI): m/z 654.2 [M+H]⁺.

Example 3/43 Step a (R)-Methyl3-(5-(4-(cyclobutylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(500 mg, 1.49 mmol, Intermediate 2) and(R)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(700 mg, 1.69 mmol, Intermediate 4/22) in DME (20 mL) was addedpotassium carbonate (400 mg, 2.89 mmol), pivalic acid (85 mg, 0.83mmol), tricyclohexylphosphine tetrafluoroborate (100 mg, 0.27 mmol), andpalladium acetate (100 mg, 0.45 mmol). The mixture was stirred at 115°C. for 2 h. After cooling to room temperature, water (25 mL) and EtOAc(15 mL) were added. The layers were mixed and separated and the aqueouslayer was further extracted with additional ethyl acetate (3×15 mL). Thecombined organic layers were washed with water (3×10 mL) and then brine(10 mL). After concentration, the resulting residue was purified by FCCon silica gel (PE/EtOAc=15:1 ramping to 3:1) to provide the titlecompound.

Example 3/43(R)-3-(5-(4-(cyclobutylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

A mixture of (R)-methyl3-(5-(4-(cyclobutylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(600 mg, 0.90 mmol, Example 3/43, step a) and LiOH (190 mg, 7.93 mmol)in MeOH (6 mL), THF (6 mL), and water (3 mL) was stirred at roomtemperature for 6 h. After concentration, the residue was partitionedbetween water (12 mL) and EtOAc (6 mL). The layers were separated andthe aqueous layer was extracted with additional EtOAc (2×6 mL). Thecombined organic layers were washed with brine and concentrated todryness. Dissolution into EtOAc (5 mL), treatment with heptane (20 mL),and concentration to dryness provided the title compound as a solid. ¹HNMR (400 MHz, CDCl₃) δ 8.11-8.02 (m, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.67(t, J=52.5 Hz, 1H), 5.34-5.23 (m, 1H), 3.98-3.87 (m, 1H), 3.28 (s, 2H),2.78-2.50 (m, 3H), 2.01-1.47 (m, 8H), 1.43 (s, 6H), 1.12 (t, J=7.4 Hz,3H). MS (ESI): m/z 655.1 [M+H]⁺.

Example 4 Step a (S)-Ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazole-2-carboxylate

To a solution of ethyl4-(2-methoxy-2-methylpropyl)thiazole-2-carboxylate (490 mg, 2.02 mmol,Intermediate 1/4) and(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(830 mg, 2.00 mmol, Intermediate 4/3) in DMA (30 mL) was addedP(Cy)₃.HBF₄ (200 mg, 0.54 mmol), pivalic acid (200 mg, 2.0 mmol),Pd(OAc)₂ (200 mg, 0.90 mmol), and K₂CO₃ (550 mg, 4.0 mmol) under N₂atmosphere. The mixture was heated to 110° C. and stirred overnight. Themixture was allowed to cool to rt and then water (50 mL) and EtOAc (50mL) were added. The layers were separated, the aqueous layer wasextracted with EtOAc (3×50 mL) and the combined organic layers wereconcentrated to dryness. The residue was purified by preparative TLC(PE/EtOAc=1:1) to afford the title compound as a brown oil.

Example 4 Step b(S)-2,3-Dichloro-4-(2-(hydrazinecarbonyl)-4-(2-methoxy-2-methylpropyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

A mixture of (S)-ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazole-2-carboxylate(550 mg, 0.96 mmol, Example 4, step a) and hydrazine monohydrate (0.5mL) in ethanol (10 mL) was stirred at 50° C. for 4 h. The mixture wasconcentrated to dryness and the residue was purified by preparative TLC(EtOAc) to give the title compound as a brown solid.

Example 4 Step c (S)-Methyl4-(2-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazole-2-carbonyl)hydrazinyl)-2,2-dimethyl-4-oxobutanoate

A solution of(S)-2,3-dichloro-4-(2-(hydrazinecarbonyl)-4-(2-methoxy-2-methylpropyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(440 mg, 0.78 mmol, Example 4, step b),4-methoxy-3,3-dimethyl-4-oxobutanoic acid (220 mg, 1.4 mmol), HATU (530mg, 1.4 mmol), and TEA (0.5 mL) in acetonitrile (10 mL) was stirred atrt for 2 h. The mixture was poured into water (20 mL) and extracted withEtOAc (4×30 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by preparative TLC (DCM/MeOH=10:1) to afford thetitle compound as a colorless solid.

Example 4 Step d (S)-Methyl3-(5-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

A mixture of (S)-methyl4-(2-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazole-2-carbonyl)hydrazinyl)-2,2-dimethyl-4-oxobutanoate(159 mg, 0.226 mmol, Example 4, step c), TsCl (87 mg, 0.46 mmol) and TEA(0.1 mL) in DCM (5 mL) was stirred at rt overnight. The mixture waspoured into water (10 mL) and extracted with EtOAc (3×8 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby preparative TLC (EtOAc/PE=4:1) to give the title compound as acolorless solid.

Example 4(S)-3-(5-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

A mixture of (S)-methyl3-(5-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(91 mg, 0.13 mmol, Example 4, step d) and LiOH.H₂O (11 mg, 0.26 mmol) inMeOH (4 mL) and water (2 mL) was stirred at rt overnight. The mixturewas concentrated to dryness, water was added (10 mL) and the aqueouslayer was extracted with EtOAc (3×8 mL). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by preparative HPLC togive the title compound as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆):δ ppm 12.58 (br s, 1H), 9.19 (d, J=9.2 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H),7.78 (d, J=8.0 Hz, 1H), 3.95-3.89 (m, 1H), 3.22 (s, 2H), 2.89 (s, 3H),2.84 (s, 2H), 1.72-1.54 (m, 2H), 1.28 (s, 6H), 1.01 (s, 6H), 0.87 (t,J=7.2 Hz, 3H). MS (ESI): m/z 673.0 [M+H]⁺.

Example 4/1(S)-3-(5-(4-(Cyclobutylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 4 using in step a ethyl4-(cyclobutylmethyl)thiazole-2-carboxylate (Intermediate 1) in place of4-(2-methoxy-2-methylpropyl)thiazole-2-carboxylate and(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 8.07 (t, J=7.6 Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 6.68 (t, J=52.8 Hz, 1H), 5.41 (d, J=10.0 Hz, 1H), 3.95-3.88 (m,1H), 3.29 (s, 2H), 2.70-2.59 (m, 3H), 1.96-1.54 (m, 8H), 1.43 (s, 6H),1.11 (t, J=7.2 Hz, 3H). MS (ESI): m/z 655.1 [M+H]⁺.

An Alternative Synthesis of Example 4/1

The title compound was prepared as described for the synthesis ofExample 3/43 using in step a(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4) in place of(R)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide.

Example 4/2(S)-3-(5-(4-((3,3-Difluorocyclobutyl)methyl)-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 4 using in step a ethyl4-(3,3-difluorocyclobutyl)methyl)thiazole-2-carboxylate (Intermediate1/9) in place of 4-(2-methoxy-2-methylpropyl)thiazole-2-carboxylate and(S)-4-bromo-N-(1,1,1-trifluorobutan-2-yl)naphthalene-1-sulfonamide(Intermediate 4/8) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 8.71 (d, J=8.8 Hz, 1H), 8.32 (d, J=7.6Hz, 1H), 7.33-7.71 (m, 2H), 7.63-7.54 (m, 2H), 5.25 (br s, 1H), 3.86 (t,J=3.2 Hz, 1H), 3.29 (s, 2H), 2.73 (br s, 2H), 2.50-2.47 (m, 3H),2.03-1.97 (m, 2H), 1.89-1.82 (m, 1H), 1.59-1.52 (m, 1H), 1.40 (s, 6H),0.97 (t, J=6.8 Hz, 3H). MS (ESI): m/z 673.1 [M+H]⁺.

Example 5 Step a trans-Methyl3-(2-(4-(cyclobutylmethyl)thiazole-2-carbonyl)hydrazinecarbonyl)cyclobutanecarboxylate

A solution of 4-(cyclobutylmethyl)thiazole-2-carbohydrazide (260 mg,1.23 mmol, Intermediate 2, step a),trans-3-(methoxycarbonyl)cyclobutanecarboxylic acid (395 mg, 2.5 mmol),HATU (950 mg, 2.5 mmol), and TEA (0.8 mL) in acetonitrile (12 mL) wasstirred at rt for 2 h. The mixture was poured into water (30 mL) andextracted with EtOAc (4×30 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness. The residue was purified by FCC on silica gel (PE/EtOAc=1:2) toafford the title compound as a yellow solid.

Example 5 Step b trans-Methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)cyclobutanecarboxylate

A mixture of trans-methyl3-(2-(4-(cyclobutylmethyl)thiazole-2-carbonyl)hydrazinecarbonyl)cyclobutanecarboxylate(185 mg, 0.526 mmol, Example 5, step a), TsCl (475 mg, 2.49 mmol) andTEA (0.8 mL) in DCM (5 mL) was stirred at rt overnight. The mixture waspoured into water (20 mL) and extracted with EtOAc (3×25 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby FCC on silica gel (PE/EtOAc=2:1) to give the title compound as ayellow oil.

Example 5trans-3-(5-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N—((S)-1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)cyclobutanecarboxylicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a trans-methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)cyclobutanecarboxylate(Example 5, step b) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.11 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 5.42 (brs, 1H), 4.14-3.98 (m, 2H), 3.46-3.42 (m, 1H), 2.87-2.83 (m, 4H),2.75-2.64 (m, 3H), 1.99-1.95 (m, 2H), 1.82-1.68 (m, 2H), 1.57-1.47 (m,2H), 1.44 (d, J=6.8 Hz, 3H). MS (ESI): m/z 639.0 [M+H]⁺.

Example 6 Step a (S)-Ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(hydroxymethyl)thiazole-2-carboxylate

A mixture of ethyl 4-(hydroxymethyl)thiazole-2-carboxylate (0.94 g, 5.0mmol, Intermediate 1/7),(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(2.1 g, 5.0 mmol, Intermediate 4/3), Pd(OAc)₂ (400 mg, 1.8 mmol),P(Cy)₃.HBF₄ (400 mg, 1.1 mmol), PivOH (400 mg, 3.9 mmol), and Na₂CO₃(1.1 g, 10 mmol) in DMA (30 mL) was heated at 90° C. overnight, cooledto rt, poured into water (150 mL), and extracted with EtOAc (70 mL×3).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, concentrated to dryness, and purified by FCC on silicagel (PE/EtOAc=2:1) to give the title compound as a brown solid.

Example 6 Step b (S)-Ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-formylthiazole-2-carboxylate

A solution of (S)-ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(hydroxymethyl)thiazole-2-carboxylate(520 mg, 1.0 mmol, Example 6, step a) and MnO₂ (870 mg, 10.0 mmol) inDCM (10 mL) was stirred at rt overnight. The reaction mixture was thenfiltered through a pad of Celite®, and the filtrate was concentrated todryness to give the title compound as a brown oil, which was useddirectly in the next step.

Example 6 Step c

(S)-Ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazole-2-carboxylate

A solution of crude (S)-ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-formylthiazole-2-carboxylate(477 mg, 0.919 mmol, Example 6, step b), 3,3-difluoropiperidine (220 mg,1.84 mmol), and HOAc (3 drops) in MeOH (10 mL) was stirred at rtovernight. NaBH(OAc)₃ (390 mg, 1.84 mmol) was added and the mixture wasstirred at rt for 2 h. The reaction mixture was then diluted with water(20 mL) and extracted with EtOAc (20 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered,concentrated to dryness, and purified by FCC on silica gel(PE/EtOAc=3:2) to give the title compound as a brown gel.

Example 6 Step d(S)-2,3-Dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(hydrazinecarbonyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

A solution of (S)-ethyl5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazole-2-carboxylate(350 mg, 0.56 mmol, Example 6, step c) and hydrazine hydrate (0.4 mL) inEtOH (10 mL) was stirred at 50° C. for 4 h, concentrated to dryness, andpurified by preparative TLC (EtOAc) to give the title compound as abrown solid.

Example 6 Step e(S)-2,3-Dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(2-(2-hydroxy-2-methylpropanoyl)hydrazinecarbonyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

A solution of(S)-2,3-dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(hydrazinecarbonyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(130 mg, 0.21 mmol, Example 6, step d), 2-hydroxy-2-methylpropanoic acid(42 mg, 0.40 mmol), HATU (114 mg, 300 μmol), and TEA (0.1 mL) in MeCN (5mL) was stirred at rt for 2 h. The reaction mixture was then poured intowater (20 mL) and extracted with EtOAc (20 mL×4). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered,concentrated to dryness, and purified by preparative TLC (DCM/MeOH=10:1)to afford the title compound as a colorless solid.

Example 6(S)-2,3-Dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide

A solution of(S)-2,3-dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(2-(2-hydroxy-2-methylpropanoyl)hydrazinecarbonyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(75 mg, 0.11 mmol, Example 6, step e), TsCl (42 mg, 0.22 mmol), and TEA(0.05 mL) in DCM (10 mL) was stirred at rt overnight. The reactionmixture was then poured into water (10 mL) and extracted with EtOAc (8mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, concentrated to dryness, and purified bypreparative TLC (EtOAc/PE=4:1) to give the title compound as a colorlesssolid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 9.02 (br s, 1H), 8.05 (d, J=8.0Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 6.13 (s, 1H), 3.95-3.85 (m, 1H), 3.71(s, 2H), 2.58-2.54 (m, 2H), 2.30-2.26 (m, 2H), 1.79-1.55 (m, 10H),1.45-1.35 (m, 2H), 0.87 (t, J=7.2 Hz, 3H). MS (ESI): m/z 678.0 [M+H]⁺.

Example 7 Step a (S)-Methyl4-(2-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazole-2-carbonyl)hydrazinyl)-2,2-dimethyl-4-oxobutanoate

A solution of(S)-2,3-dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(hydrazinecarbonyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(130 mg, 0.21 mmol, Example 6, step d),4-methoxy-3,3-dimethyl-4-oxobutanoic acid (64 mg, 0.40 mmol), HATU (150mg, 0.40 mmol), and TEA (0.1 mL) in MeCN (5 mL) was stirred at rt for 2h. The reaction mixture was then poured into water (20 mL) and extractedwith EtOAc (20 mL×3). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered, concentrated to dryness,and purified by preparative TLC (DCM/MeOH=10:1) to afford the titlecompound as a colorless solid.

Example 7 Step b (S)-Methyl3-(5-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

A solution of (S)-methyl4-(2-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazole-2-carbonyl)hydrazinyl)-2,2-dimethyl-4-oxobutanoate(105 mg, 0.140 mmol, Example 7, step a), TsCl (42 mg, 0.22 mmol), andTEA (0.05 mL) in DCM (10 mL) was stirred at rt overnight. The reactionmixture was then poured into water (10 mL) and extracted with EtOAc (8mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, concentrated to dryness, and purified bypreparative TLC (EtOAc/PE=2:1) to give the title compound as a colorlesssolid.

Example 7(S)-3-(5-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

A solution of (S)-methyl3-(5-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(63 mg, 96 μmol, Example 7, step b) and LiOH.H₂O (11 mg, 0.27 mmol) inMeOH (4 mL) and water (2 mL) was stirred at rt overnight. The reactionmixture was then concentrated to dryness, diluted with water (10 mL),adjusted to pH 7 with 0.1 M aqueous HCl and extracted with EtOAc (8mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, concentrated to dryness, and purified bypreparative HPLC to give the title compound as a colorless solid. ¹H NMR(400 MHz, CDCl₃): δ ppm 8.10 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H),5.56 (d, J=10.0 Hz, 1H), 4.08 (s, 2H), 3.90-3.87 (m, 1H), 3.27 (s, 2H),3.12 (t, J=2.8 Hz, 2H), 2.95 (br s, 2H), 1.99-1.80 (m, 5H), 1.66-1.60(m, 1H), 1.39 (s, 6H), 1.11 (t, J=7.2 Hz, 3H). MS (ESI): m/z 720.0[M+H]⁺.

Example 8 Step a (S)-Methyl3-(5-(4-(hydroxymethyl)-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

To a solution of(S)-4-bromo-N-(1,1,1-trifluorobutan-2-yl)naphthalene-1-sulfonamide (790mg, 2.0 mmol, Intermediate 4/8) and methyl3-(5-(4-(hydroxymethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(600 mg, 2.0 mmol, Intermediate 2/5) in DMA (30 mL) was addedP(Cy)₃.HBF₄ (160 mg, 0.44 mmol), PivOH (160 mg, 1.6 mmol), Pd(OAc)₂ (160mg, 0.71 mmol), and K₂CO₃ (560 mg, 4 mmol) under a N₂ atmosphere, andthe mixture was stirred at 110° C. overnight. The reaction mixture wasthen allowed to cool to rt, diluted with water (60 mL), and extractedwith EtOAc (60 mL×4). The combined organic layers were concentrated todryness and purified by preparative TLC (PE/EtOAc=1:1) to afford thetitle compound as a brown solid.

Example 8 Step b (S)-Methyl3-(5-(4-formyl-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(5-(4-(hydroxymethyl)-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(620 mg, 1.0 mmol, Example 8, step a) in DCM (20 mL) was added activatedMnO₂ (440 mg, 5.0 mmol) and the black suspension was stirred at rt for 2h. The reaction mixture was then filtered through a pad of Celite® andconcentrated to dryness to give the crude title compound as a brownsolid, which was used directly in the next step.

Example 8 Step c Methyl3-(5-(4-(((R)-3-fluoropiperidin-1-yl)methyl)-5-(4-(N—((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(5-(4-formyl-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(240 mg, 0.39 mmol, Example 8, step b) in THF (8 mL) was added(R)-3-fluoropiperidine (83 mg, 0.80 mmol) and HOAc (3 drops) and themixture was stirred at rt overnight. NaBH(OAc)₃ (170 mg, 0.80 mmol) wasadded in portions and the mixture was stirred for 4 h. The reactionmixture was then diluted with ice and extracted with EtOAc (20 mL×3).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, concentrated to dryness, and purified by preparativeTLC (PE/EtOAc=2/3) to give the title compound as a colorless solid.

Example 83-(5-(4-(((R)-3-Fluoropiperidin-1-yl)methyl)-5-(4-(N—((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

A solution of methyl3-(5-(4-(((R)-3-fluoropiperidin-1-yl)methyl)-5-(44N-((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoate(80 mg, 0.12 mmol, Example 8, step c) and LiOH.H₂O (25 mg, 0.60 mmol) inMeOH (4 mL) and water (2 mL) was stirred at rt overnight. The reactionmixture was then concentrated to dryness, diluted with water (10 mL),and extracted with EtOAc (8 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered, concentratedto dryness, and purified by preparative HPLC to give the title compoundas a colorless solid. ¹H NMR (400 MHz, CD₃OD): δ ppm 8.87 (d, J=6.4 Hz,1H), 8.35 (d, J=6.0 Hz, 1H), 7.87-7.69 (m, 4H), 4.31 (d, J=38.4 Hz, 1H),3.88-3.85 (m, 1H), 3.58 (s, 2H), 3.28 (s, 2H), 2.66-2.60 (m, 1H),2.33-2.25 (m, 2H), 2.13-2.12 (m, 1H), 1.76-1.53 (m, 4H), 1.45-1.37 (m,7H), 1.25-1.23 (m, 1H), 0.79 (t, J=6.0 Hz, 3H). MS (ESI): m/z 684.0[M+H]⁺.

Example 8/1(S)-3-(5-(4-((3,3-Difluoropiperidin-1-yl)methyl)-5-(4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)naphthalen-1-yl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 8, using in step c 3,3-difluoropiperidine in place of(R)-3-fluoropiperidine. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.70 (d, J=6.8Hz, 1H), 8.35 (d, J=6.0 Hz, 1H), 7.79-7.75 (m, 2H), 7.70-7.65 (m, 2H),5.35 (d, J=6.8 Hz, 1H), 4.22-4.14 (m, 2H), 3.89-3.86 (m, 1H), 3.34-3.24(m, 4H), 3.12 (s, 2H), 1.99-1.83 (m, 5H), 1.61-1.55 (m, 1H), 1.43 (s,6H), 0.99 (t, J=6.0 Hz, 3H). MS (ESI): m/z 702.1 [M+H]⁺.

Example 8/23-(5-(5-(2,3-Dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 8, using in step a2-(4-bromo-2,3-dichlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 6) in place of(S)-4-bromo-N-(1,1,1-trifluorobutan-2-yl)naphthalene-1-sulfonamide andin step c 3,3-difluoropiperidine in place of (R)-3-fluoropiperidine. ¹HNMR (400 MHz, CDCl₃): δ ppm 7.85 (br s, 1H), 7.49 (d, J=7.2 Hz, 1H),4.23 (s, 2H), 3.40-3.27 (m, 4H), 3.11 (br s, 2H), 2.00-1.95 (m, 2H),1.95-1.85 (m, 2H), 1.40 (s, 6H). MS (ESI): m/z 697.1 [M+H]⁺.

Example 8/3(R)-3-(5-(5-(2,3-Dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-((3-fluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 8, using in step a2-(4-bromo-2,3-dichlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 6) in place of(S)-4-bromo-N-(1,1,1-trifluorobutan-2-yl)naphthalene-1-sulfonamide. ¹HNMR (400 MHz, CDCl₃): δ ppm 7.75 (br s, 1H), 7.44 (d, J=8.4 Hz, 1H),4.49-4.35 (m, 1H), 4.28 (br s, 1H), 3.69-3.57 (m, 2H), 3.26 (s, 2H),2.55-2.21 (m, 4H), 1.65-1.59 (m, 3H), 1.31 (s, 6H), 1.30-1.27 (m, 1H).MS (ESI): m/z 679.1 [M+H]⁺.

Example 9 Step a Methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropanoate

A mixture of methyl4-(2-(4-(cyclobutylmethyl)thiazole-2-carbonyl)hydrazinyl)-2,2-dimethyl-4-oxobutanoate(220 mg, 0.63 mmol, Intermediate 2, step b) and Lawesson reagent (283mg, 0.700 mmol) in toluene (2.5 mL) was stirred at 110° C. overnight.The mixture was poured into water (10 mL) and extracted with EtOAc (3×15mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by preparative TLC (PE/EtOAc=2:1) to give the title compound asa yellow solid.

Example 9(S)-3-(5-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropanoate(Example 9, step a) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.09 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 5.51 (d,J=10.0 Hz, 1H), 4.13-4.07 (m, 1H), 3.48 (s, 2H), 2.66-2.62 (m, 3H),2.00-1.96 (m, 2H), 1.79-1.69 (m, 2H), 1.56-1.52 (m, 2H), 1.43 (d, J=7.2Hz, 3H), 1.40 (s, 6H). MS (ESI) m/z 657.0 [M+H]⁺.

Example 10 Step a 5-Bromo-4-(cyclohexylmethyl)thiazole-2-carboxamide

A stream of NH₃ gas was passed through anhydrous EtOH (70 mL) at −20° C.for 7 min. Then a solution of ethyl5-bromo-4-(cyclohexylmethyl)thiazole-2-carboxylate (1.00 g, 3.00 mmol,prepared as described in WO2013/178362, Example 6, step 3) in EtOH (5mL) was added, and the solution was stirred at 80° C. overnight. Theresulting solution was concentrated to dryness to give the titlecompound as a pale yellow solid.

Example 10 Step b 5-Bromo-4-(cyclohexylmethyl)thiazole-2-carbonitrile

To a solution of 5-bromo-4-(cyclohexylmethyl)thiazole-2-carboxamide (660mg, 2.17 mmol, Example 10, step a) and TEA (1.01 g, 10.9 mmol) inanhydrous DCM (5 mL) at 0° C. under N₂ was added TFAA (1.37 g, 6.51mmol) and the solution was stirred at 0° C. for 2 h. The resultingsolution was quenched with water and extracted with DCM twice. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness to give the title compoundas a yellow solid.

Example 10 Step c5-Bromo-4-(cyclohexylmethyl)-N′-hydroxythiazole-2-carboximidamide

To a solution of 5-bromo-4-(cyclohexylmethyl)thiazole-2-carbonitrile(600 mg, 2.10 mmol, Example 10, step b) and TEA (636 mg, 6.30 mmol) inanhydrous EtOH (5 mL) was added hydroxylamine hydrochloride (438 mg,6.30 mmol), and the solution was heated to reflux overnight. After itwas allowed to cool to rt, the resulting solution was concentrated todryness and purified by FCC on silica gel (PE/EtOAc=10/1) to give thetitle compound as a colorless solid.

Example 10 Step dN′-Acetoxy-5-bromo-4-(cyclohexylmethyl)thiazole-2-carboximidamide

To a stirred solution of5-bromo-4-(cyclohexylmethyl)-N-hydroxythiazole-2-carboximidamide (460mg, 1.44 mmol, Example 10, step c) in pyridine (5 mL) was added Ac₂O(300 mg, 2.89 mmol), and the solution was heated at 50° C. overnight.After it was allowed to cool to rt, the resulting solution wasconcentrated to dryness and purified by FCC on silica gel (PE/EtOAc=6/1)to give the title compound as an off-white solid.

Example 10 Step e3-(5-Bromo-4-(cyclohexylmethyl)thiazol-2-yl)-5-methyl-1,2,4-oxadiazole

To a solution ofN-acetoxy-5-bromo-4-(cyclohexylmethyl)thiazole-2-carboximidamide (472mg, 1.31 mmol, Example 10, step d) in a mixture of DMF (5 mL) and water(1 mL) was added NaOAc (108 mg, 1.31 mmol), and the solution was heatedat reflux temperature for 5 h. After it was allowed to cool to rt, thesolution was quenched with water and extracted with DCM twice. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, concentrated to dryness, and purified by FCC on silicagel (PE/EtOAc=8/1) to give the title compound as a colorless solid.

Example 10N-(tert-Butyl)-4-(4-(cyclohexylmethyl)-2-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-5-yl)naphthalene-1-sulfonamide

A solution of3-(5-bromo-4-(cyclohexylmethyl)thiazol-2-yl)-5-methyl-1,2,4-oxadiazole(100 mg, 0.29 mmol, Example 10, step e),N-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-sulfonamide(142 mg, 0.365 mmol, Intermediate 18), 2 M aqueous Na₂CO₃ (2.4 mL), andPd(dppf)Cl₂ (24 mg, 30 μmol) in DME (5 mL) was heated to refluxtemperature overnight under nitrogen. The resulting solution was allowedto cool to rt and diluted with EtOAc. The layers were separated, and theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered, concentrated to dryness, and purified by FCC on silica gel(PE/EtOAc=2/1) to give the title compound as a colorless solid. ¹H NMR(CD₃OD, 400 MHz): δ ppm 8.75 (d, J=8.4 Hz, 1H), 8.26 (d, J=7.6 Hz, 1H),7.71-7.55 (m, 4H), 2.62 (s, 3H), 2.38 (br s, 2H), 1.60-1.57 (m, 1H),1.44-1.38 (m, 5H), 1.05 (s, 9H), 1.00-0.87 (m, 3H), 0.61-0.53 (m, 2H).MS (ESI): m/z 525.2 [M+H]⁺.

Example 11 Step a (S)-Methyl3-(3-(4-(cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

A solution of methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(145 mg, 0.432 mmol, Intermediate 3),(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(170 mg, 0.43 mmol, Intermediate 4/2), K₂CO₃ (120 mg, 0.86 mmol),Pd(OAc)₂ (23 mg, 0.10 mmol), P(Cy)₃.HBF₄ (20 mg, 58 μmol), and PivOH (10mg, 86 μmol) in DMA (2 mL) was heated under argon at 95° C. overnight.The reaction mixture was then allowed to cool to rt, partitioned betweenEtOAc and water, and the layers were separated. The organic layer waswashed with water and brine, dried over anhydrous Na₂SO₄, filtered,concentrated to dryness, and purified by preparative TLC (EtOAc) to givethe title compound as a light-yellow solid.

Example 11(S)-3-(3-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

A mixture of (S)-methyl3-(3-(4-(cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(126 mg, 0.192 mmol, Example 11, step a) and LiOH.H₂O (43 mg, 1.0 mmol)in MeOH (2 mL) and water (1 mL) was stirred at rt overnight. The mixturewas concentrated and aqueous HCl (1 M, 10 mL) was added. The aqueousphase was extracted with EtOAc (3×8 mL) and the combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by preparative HPLC togive the title compound as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δppm 8.10 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 5.51 (d, J=8.4 Hz,1H), 4.13-4.07 (m, 1H), 3.30 (s, 2H), 2.76-2.67 (m, 3H), 1.96-1.93 (m,2H), 1.80-1.68 (m, 2H), 1.54-1.42 (m, 11H). MS (ESI): m/z 641.2 [M+H]⁺.

Example 11/1(S)-3-(3-(4-(Cyclobutylmethyl)-5-(2-(trifluoromethoxy)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a(S)-4-bromo-3-(trifluoromethoxy)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/14) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CD₃OD): δ ppm 8.03-7.99 (m, 2H), 7.84 (d, J=6.4 Hz,1H), 4.20-4.15 (m, 1H), 3.32 (s, 2H), 2.84 (d, J=6.4 Hz, 2H), 2.76-2.69(m, 1H), 1.99-1.95 (m, 2H), 1.84-1.70 (m, 2H), 1.62-1.55 (m, 2H), 1.41(s, 6H), 1.26 (d, J=5.6 Hz, 3H). MS (ESI): m/z 656.7 [M+H]⁺.

Example 11/2(S)-3-(3-(4-(Cyclohexylmethyl)-5-(8-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-5-yl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a methyl3-(3-(4-(cyclohexylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(Intermediate 3/1) in place of methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoateand (5)-5-bromo-N-(1,1,1-trifluoropropan-2-yl)iso quinoline-8-sulfonamide (Intermediate 4/16) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.11 (s, 1H), 9.34 (d, J=7.6 Hz, 1H),8.73 (d, J=4.8 Hz, 1H), 8.37 (d, J=6.0 Hz, 1H), 8.07 (d, J=6.0 Hz, 1H),7.73 (d, J=4.4 Hz, 1H), 4.22-4.16 (m, 1H), 3.30 (s, 2H), 2.42 (s, 2H),1.64-1.62 (m, 1H), 1.51-1.45 (m, 5H), 1.30 (s, 6H), 1.10-0.90 (m, 6H),0.61-0.58 (m, 2H). MS (ESI) m/z 652.2 [M+H]⁺.

Example 11/3(S)-3-(3-(4-(Cyclohexylmethyl)-5-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-8-yl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a methyl3-(3-(4-(cyclohexylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(Intermediate 3/1) in place of methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoateand(S)-8-chloro-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-5-sulfonamide(Intermediate 4/17) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CD₃OD): δ ppm 9.31 (s, 1H), 8.83-8.78 (m, 2H), 8.68 (d,J=7.6 Hz, 1H), 7.99-7.96 (m, 1H), 4.17-4.10 (m, 1H), 3.37 (s, 2H),2.60-2.40 (m, 2H), 1.78-1.74 (m, 1H), 1.58-1.52 (m, 5H), 1.42 (s, 6H),1.27 (d, J=6.8 Hz, 3H), 1.17-0.99 (m, 3H), 0.70-0.64 (m, 2H). MS (ESI):m/z 652.2 [M+H]⁺.

Example 11/4(S)-3-(3-(4-(Cyclohexylmethyl)-5-(2-(trifluoromethoxy)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a methyl3-(3-(4-(cyclohexylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(Intermediate 3/1) in place of methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoateand(S)-4-bromo-3-(trifluoromethoxy)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/14) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 7.92-7.90 (m, 2H), 7.63 (d, J=6.4 Hz,1H), 5.17 (d, J=8.0 Hz, 1H), 4.14-4.09 (m, 1H), 3.32 (s, 2H), 2.61 (d,J=5.6 Hz, 2H), 1.88-1.84 (m, 1H), 1.63-1.55 (m, 5H), 1.46-1.44 (m, 9H),1.21-1.04 (m, 3H), 0.79-0.72 (m, 2H). MS (ESI): m/z 685.1 [M+H]⁺.

Example 11/5(S)-3-(3-(4-(Cyclobutylmethyl)-5-(1-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-4-yl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a(S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-1-sulfonamide(Intermediate 4/19) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 9.02-9.00 (m, 1H), 8.49 (s, 1H),7.85-7.77 (m, 3H), 5.68 (d, J=8.8 Hz, 1H), 4.28-4.21 (m, 1H), 3.31 (s,2H), 2.71 (s, 3H), 1.92-1.87 (m, 2H), 1.73-1.69 (m, 1H), 1.62-1.58 (m,4H), 1.45-1.42 (m, 8H). MS (ESI): m/z 624.2 [M+H]⁺.

Example 11/6(S)-3-(3-(4-(Cyclobutylmethyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CD₃OD): δ ppm 8.14 (t, J=7.6 Hz, 1H), 7.48 (d, J=8.4Hz, 1H), 6.85 (t, J=52 Hz, 1H), 3.96-3.90 (m, 1H), 3.28 (s, 2H),2.73-2.67 (m, 3H), 2.00-1.95 (m, 2H), 1.88-1.57 (m, 6H), 1.37 (s, 6H),0.99 (t, J=7.2 Hz, 3H). MS (ESI): m/z 655.1 [M+H]⁺.

Example 11/7(S)-3-(3-(4-(Cyclobutylmethyl)-5-(3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)-2-(trifluoromethyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a(S)-4-bromo-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)-3-(trifluoromethyl)benzenesulfonamide(Intermediate 4/9) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CD₃OD): δ ppm 8.23 (t, J=7.6 Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 3.97-3.93 (m, 1H), 3.29 (s, 2H), 2.77-2.58 (m, 3H), 2.01-1.51(m, 8H), 1.38 (s, 6H), 1.07-0.97 (m, 3H). MS (ESI): m/z 673.1 [M+H]⁺.

Example 11/8(S)-3-(3-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a methyl3-(3-(4-(2-methoxy-2-methylpropyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(Intermediate 3/2) in place of methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/3) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 8.06 (d, J=6.4 Hz, 1H), 7.50 (d, J=6.4Hz, 1H), 5.47 (m, 1H), 3.87 (m, 1H), 3.26 (m 2H), 2.99 (s, 3H), 2.87 (s,2H), 1.92-1.88 (m, 1H), 1.64-1.56 (m, 1H), 1.32 (s, 6H), 1.12-1.06 (m,9H). MS (ESI): m/z 673.1 [M+H]⁺.

Example 11/9(S)-3-(3-(4-(Cyclohexylmethyl)-5-(3-(1-methylcyclopropyl)-5-((1,1,1-trifluoropropan-2-yl)carbamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a methyl3-(3-(4-(cyclohexylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(Intermediate 3/1) in place of methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoateand(S)-3-bromo-5-(1-methylcyclopropyl)-N-(1,1,1-trifluoropropan-2-yl)benzamide(Intermediate 10) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 7.75 (s, 1H), 7.63 (s, 1H), 7.43 (s, 1H),6.60-6.54 (m, 1H), 5.00-4.93 (m, 1H), 3.25 (s, 2H), 2.58 (d, J=6.0 Hz,2H), 1.75-1.44 (m, 12H), 1.35 (s, 6H), 1.06-1.01 (m, 3H), 0.99-0.90 (m,2H), 0.88-0.80 (m, 4H). MS 619.3 (ESI) m/z [M+H]⁺.

Example 11/10(S)-3-(3-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((1-methoxycyclobutyl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a methyl3-(3-(4-((l-methoxycyclobutyl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(Intermediate 3/4) in place of methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/3) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 8.06 (d, J=8.2 Hz, 1H), 7.54 (d, J=8.2Hz, 1H), 5.57 (d, J=9.6 Hz, 1H), 3.87 (s, 1H), 3.29 (s, 2H), 3.06 (s,2H), 2.88 (s, 3H), 2.09-2.04 (m, 4H), 1.91-1.86 (m, 1H), 1.65-1.50 (m,3H), 1.40 (s, 6H), 1.11-1.08 (m, 3H). MS (ESI): 685.0 [M+H]⁺.

Example 11/11(S)-3-(3-(5-(3-Chloro-2-(difluoromethyl)-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-4-(cyclobutylmethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 11, using in step a(S)-4-bromo-2-chloro-3-(difluoromethyl)-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/20) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide.¹H NMR (500 MHz, DMSO-d₆): δ ppm 8.24 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.5Hz, 1H), 7.21 (t, J=52.5 Hz, 1H), 4.06-4.04 (m, 1H), 3.24 (s, 2H),2.69-2.63 (m, 3H), 1.90 (br s, 2H), 1.75-1.62 (m, 2H), 1.54-1.47 (m,2H), 1.26 (s, 6H), 1.20 (d, J=7.0 Hz, 3H). MS (ESI): m/z 657.1 [M+H]⁺.

Example 12 Step a (S)-Methyl3-(3-(5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(hydroxymethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(3-(4-(hydroxymethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(122 mg, 0.410 mmol, Intermediate 3/3),(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(169 mg, 0.408 mmol, Intermediate 4), and Na₂CO₃ (87 mg, 0.82 mmol) inDMA (2 mL) was added P(Cy)₃.HBF₄ (45 mg, 0.12 mmol), PivOH (15 mg, 0.15mmol), and Pd(OAc)₂ (40 mg, 0.18 mmol) under Ar. The solution wasstirred at 95° C. overnight and then allowed to cool to rt. The reactionmixture was then diluted with EtOAc and water, and the layers wereseparated. The organic layer was washed with water and brine, dried overanhydrous Na₂SO₄, filtered, concentrated to dryness, and purified by FCCon silica gel (PE/EtOAc=1:4) to give the title compound as a yellowsolid.

Example 12 Step b (S)-Methyl3-(3-(5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-formylthiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(3-(5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(hydroxymethyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(315 mg, 500 μmol, Example 12, step a) in DCM (8 mL) was added activatedMnO₂ (260 mg, 3.00 mmol) and the mixture was stirred at rt for 2 h,filtered through a pad of Celite®, and concentrated to dryness to givethe title compound as a yellow solid.

Example 12 Step c (S)-Methyl3-(3-(5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(3-(5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-formylthiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(240 mg, 0.38 mmol, Example 12, step b) in THF (5 mL) was added3,3-difluoropiperidine (92 mg, 0.76 mmol) and HOAc (3 drops) and themixture was stirred at rt overnight. NaBH(OAc)₃ (180 mg, 0.84 mmol) wasadded portionwise and stirring was continued for an additional 4 h. Thereaction mixture was then diluted with ice and extracted with EtOAc (15mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, concentrated to dryness, and purified bypreparative TLC (PE/EtOAc=1/1) to give the title compound as a solid.

Example 12(S)-3-(3-(5-(2-(Difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

A solution of (S)-methyl3-(3-(5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoate(90 mg, 0.12 mmol, Example 12, step c) and LiOH.H₂O (27 mg, 0.64 mmol)in MeOH (8 mL) and water (4 mL) was stirred at rt overnight. Thereaction mixture was then concentrated to dryness, diluted with water(15 mL), adjusted to pH 7 with aqueous HCl (2 N) and extracted withEtOAc (8 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered, concentrated to dryness, andpurified by preparative HPLC to give the title compound as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.03 (t, J=7.6 Hz, 1H), 7.41 (d,J=8.4 Hz, 1H), 6.76 (t, J=52.8 Hz, 1H), 3.93 (br s, 1H), 3.64 (s, 2H),3.28 (s, 2H), 2.56 (t, J=11.6 Hz, 2H), 2.36 (br s, 2H), 1.95-1.89 (m,1H), 1.82-1.56 (m, 5H), 1.38 (s, 6H), 1.11 (t, J=7.6 Hz, 3H). MS (ESI):m/z 720.1 [M+H]⁺.

Example 12/1(S)-3-(3-(5-(2,3-Dichloro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-((3,3-difluoropiperidin-1-yl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 12, using in step a(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/3) in place of(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ ppm 8.05 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 5.42 (br s, 1H), 3.92-3.86 (m, 1H), 3.68 (s, 2H), 3.28 (s, 2H),2.60-2.54 (m, 2H), 2.36 (s, 2H), 1.93-1.86 (m, 1H), 1.88-1.75 (m, 5H),1.35 (s, 6H), 1.09 (t, J=7.2 Hz, 3H). MS (ESI): m/z 720.0 [M+H]⁺.

Example 12/23-(3-(5-(2,3-Dichloro-4-(N—((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(((S)-4,4-difluoro-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 12, using in step a(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide(Intermediate 4/3) in place of(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamideand in step c (S)-4,4-difluoro-2-methylpyrrolidine hydrochloride(Intermediate 16, salt converted to free base with TEA prior to thecoupling) in place of 3,3-difluoropiperidine. ¹H NMR (400 MHz, CDCl₃): δppm 8.05 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 5.44 (br s, 1H),4.01 (d, J=13.2 Hz, 1H), 3.97-3.89 (m, 1H), 3.47 (d, J=13.2 Hz, 1H),3.29 (s, 2H), 3.18-3.15 (m, 1H), 2.71-2.60 (m, 2H), 2.28-2.24 (m, 1H),1.93-1.91 (m, 1H), 1.76-1.62 (m, 2H), 1.38 (s, 6H), 1.12 (t, J=7.2 Hz,3H), 0.97 (d, J=6.0 Hz, 3H). MS (ESI): m/z 720.1 [M+H]⁺.

Example 12/33-(3-(4-(((S)-4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N—((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 12, using in step c (S)-4,4-difluoro-2-methylpyrrolidinehydrochloride (Intermediate 16, salt converted to free base with TEAprior to the coupling) in place of 3,3-difluoropiperidine. ¹H NMR (400MHz, CDCl₃): δ ppm 8.04 (d, J=7.2 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 6.72(t, J=52.8 Hz, 1H), 3.92 (d, J=13.6 Hz, 1H), 3.43 (d, J=10.8 Hz, 1H),3.28 (s, 2H), 3.19-3.10 (m, 2H), 2.69-2.62 (m, 2H), 2.29-2.23 (m, 1H),1.95-1.59 (m, 3H), 1.38 (s, 6H), 1.13 (t, J=7.2 Hz, 3H), 0.90 (d, J=6.0Hz, 3H). MS (ESI): m/z 720.2 [M+H]⁺.

Example 12/43-(3-(5-(2-(Difluoromethyl)-3-fluoro-4-(N—((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(((S)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 12, using in step c (S)-2-methylpyrrolidine in place of3,3-difluoropiperidine. ¹H NMR (500 MHz, CDCl₃): δ ppm 8.05 (t, J=7.5Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 6.73 (t, J=52.5 Hz, 1H), 4.02-3.91 (m,2H), 3.53 (d, J=13.5 Hz, 1H), 3.25 (s, 2H), 3.16-3.14 (m, 1H), 2.67-2.64(m, 1H), 2.48-2.44 (m, 1H), 1.92-1.89 (m, 2H), 1.76-1.74 (m, 1H),1.65-1.62 (m, 2H), 1.47-1.44 (m, 1H), 1.33 (d, J=10.5 Hz, 6H), 1.10 (t,J=7.5 Hz, 3H), 1.01 (d, J=6.5 Hz, 3H). MS (ESI): m/z 684.2 [M+H]⁺.

Example 12/53-(3-(4-(((S)-3,3-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N—((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 12, using in step c (S)-3,3-difluoro-2-methylpyrrolidine(Intermediate 17, salt converted to free base with TEA prior to thecoupling) in place of 3,3-difluoropiperidine. ¹H NMR (500 MHz, CDCl₃): δppm 8.04 (t, J=7.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.84-6.62 (m, 1H),3.94-3.84 (m, 2H), 3.43-3.40 (m, 1H), 3.30-3.24 (m, 2H), 2.92-2.91 (m,1H), 2.54-2.51 (m, 1H), 2.36-2.30 (m, 1H), 2.14-2.09 (m, 2H), 1.94-1.91(m, 1H), 1.66-1.58 (m, 1H), 1.36 (s, 6H), 1.12 (t, J=7.5 Hz, 3H),0.91-0.86 (m, 3H). MS (ESI): m/z 720.0 [M+H]⁺.

Example 12/6(S)-3-(3-(4-((4,4-Difluoro-2,2-dimethylpyrrolidin-1-yl)methyl)-5-(2-(difluoromethyl)-3-fluoro-4-(N-(1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 12, using in step c 4,4-difluoro-2,2-dimethylpyrrolidine inplace of 3,3-difluoropiperidine. ¹H NMR (500 MHz, CDCl₃): δ ppm 8.03 (t,J=7.8 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.70 (t, J=52.5 Hz, 1H),3.94-3.91 (m, 1H), 3.62-3.57 (m, 2H), 3.27 (s, 2H), 2.97 (t, J=13.7 Hz,2H), 2.03-1.90 (m, 3H), 1.65-1.58 (m, 1H), 1.35 (s, 6H), 1.12 (t, J=7.5Hz, 3H), 0.90 (s, 6H). MS (ESI): m/z 734.0 [M+H]⁺.

Example 12/73-(3-(5-(2-(Difluoromethyl)-3-fluoro-4-(N—((S)-1,1,1-trifluorobutan-2-yl)sulfamoyl)phenyl)-4-(((R)-2-(fluoromethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 12, using in step c (R)-2-(fluoromethyl)pyrrolidine in place of3,3-difluoropiperidine. ¹H NMR (500 MHz, CDCl₃): δ ppm 8.03 (t, J=7.5Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 6.69 (t, J=52.5 Hz, 1H), 5.31 (br s,1H), 4.19-3.92 (m, 4H), 3.67 (d, J=13.5 Hz, 1H), 3.28 (s, 2H), 2.90-2.83(m, 2H), 2.39-2.34 (m, 1H), 1.93-1.82 (m, 2H), 1.68-1.63 (m, 3H),1.48-1.45 (m, 1H), 1.39 (d, J=1.5 Hz, 6H), 1.11 (t, J=7.5 Hz, 3H). MS(ESI): m/z 702.2 [M+H]⁺.

Example 13 Step a5-(5-Bromo-4-(cyclohexylmethyl)thiazol-2-yl)-3-methyl-1,2,4-oxadiazole

To a stirred solution of ethyl5-bromo-4-(cyclohexylmethyl)thiazole-2-carboxylate (200 mg, 0.602 mmol,prepared as described in WO2013/178362, Example 6, step 3) in toluene(10 mL) was added N-hydroxyacetimidamide (67 mg, 0.90 mmol), and K₂CO₃(126 mg, 0.904 mmol), and the solution was refluxed for 24 h. Aftercooling to rt, the resulting solution was diluted with EtOAc and water.The organic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered, concentrated to dryness, and purified by FCC on silica gel(EtOAc/PE=1/5) to give the title compound as a colorless solid.

Example 13N-(tert-Butyl)-4-(4-(cyclohexylmethyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-5-yl)naphthalene-1-sulfonamide

A solution of5-(5-bromo-4-(cyclohexylmethyl)thiazol-2-yl)-3-methyl-1,2,4-oxadiazole(100 mg, 0.292 mmol, Example 13, step a),N-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-sulfonamide(142 mg, 0.366 mmol, Intermediate 18), Pd(dppf)Cl₂ (24 mg, 29 μmol), andNa₂CO₃ (2 M in water, 1.6 mL, 3.2 mmol) in DME (5 mL) was purged withnitrogen for 15 min and then heated to reflux overnight. After allowingto cool to rt, the resulting solution was diluted with EtOAc and water.The layers were separated, and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, concentrated to dryness, and purified by FCCon silica gel (EtOAc/PE=1/1) to give the title compound as a colorlesssolid. ¹H NMR (400 MHz, DMSO-d₆): 6 ppm 8.82 (d, J=8.2 Hz, 1H), 8.29 (d,J=8.2 Hz, 1H), 7.95 (s, 1H), 7.80-7.75 (m, 3H), 7.71-7.67 (m, 1H), 2.48(s, 3H), 2.43-2.42 (m, 2H), 1.65-1.61 (m, 1H), 1.46-1.44 (m, 5H), 1.09(s, 9H), 1.04-0.85 (m, 3H), 0.67-0.59 (m, 2H). MS (ESI): m/z 525.2[M+H]⁺.

Example 14 Step a (4-(Cyclobutylmethyl)thiazol-2-yl)methanol

To a solution of ethyl 4-(cyclobutylmethyl)thiazole-2-carboxylate (600mg, 2.7 mmol, Intermediate 1) in MeOH (10 mL) was slowly added NaBH₄(310 mg, 8.1 mmol) at 0° C., and the mixture was stirred at thistemperature for 6 h. Water was then added, and the mixture was extractedwith EtOAc three times. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness to give the title compound as a brown oil.

Example 14 Step b 4-(Cyclobutylmethyl)thiazole-2-carbaldehyde

A solution of (4-(cyclobutylmethyl)thiazol-2-yl)methanol (330 mg, 1.8mmol, Example 14, step a) and IBX (1.0 g, 3.6 mmol) in acetone (10 mL)was heated to reflux overnight. The mixture was allowed to cool,filtered, and the filtrate was concentrated to dryness to give the titlecompound as a brown oil.

Example 14 Step c 4-(Cyclobutylmethyl)thiazole-2-carbaldehyde oxime

A suspension of 4-(cyclobutylmethyl)thiazole-2-carbaldehyde (280 mg, 1.6mmol, Example 14, step b), NH₂OH.HCl (220 mg, 3.2 mmol), Na₂CO₃ (340 mg,3.2 mmol) in EtOH.water (20 mL, 5:1 v/v) was stirred at rt for 1 h. Thereaction was concentrated to dryness, and the residue was diluted withwater and then extracted with EtOAc. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to drynessto afford the title compound.

Example 14 Step d Methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)isoxazol-5-yl)-2,2-dimethylpropanoate

A mixture of 4-(cyclobutylmethyl)thiazole-2-carbaldehyde oxime (250 mg,1.4 mmol, Example 14, step c) and methyl 2,2-dimethylpent-4-ynoate (190mg, 1.4 mmol) in DCM (5 mL) was cooled to 0° C. A sodium hypochloritesolution (5% chlorine, 5 mL, 4 mmol) was added dropwise to the solution.The mixture was stirred overnight at rt, and then DCM (20 mL) was added.The layers were separated, and the organic layer was washed sequentiallywith water, 1 M aqueous HCl, saturated aqueous NaHCO₃, and brine, driedover anhydrous MgSO₄, filtered and concentrated to dryness. The residuewas purified by FCC on silica gel (PE/EtOAc=8:1) to give the titlecompound as a colorless solid.

Example 14(S)-3-(3-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)isoxazol-5-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)isoxazol-5-yl)-2,2-dimethylpropanoicacid (Example 14, step d) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CD₃OD): δ ppm 8.18 (d, J=6.6 Hz, 1H), 7.65 (d, J=6.8 Hz, 1H), 6.77 (s,1H), 4.13-4.10 (m, 1H), 3.16 (s, 2H), 2.74-2.68 (m, 3H), 2.02-1.98 (m,2H), 1.83-1.79 (m, 2H), 1.74-1.72 (m, 2H), 1.60-1.56 (m, 3H), 1.37 (d,J=5.6 Hz, 3H), 1.30 (m, 3H). MS (ESI): m/z 640.0 [M+H]⁺.

Example 15 Step a 4-(Cyclobutylmethyl)thiazol-2-amine

Thiourea (71 mg, 0.93 mmol), 1-bromo-3-cyclobutylpropan-2-one (177 mg,0.927 mmol, Intermediate 1, step d) in EtOH (3 mL) was stirred at 75° C.overnight. Water was added, and the mixture was extracted with EtOActhree times. The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated to dryness to give aresidue, which was purified by FCC on silica gel (PE/EtOAc=8:1) toafford the title compound.

Example 15 Step b 2-Bromo-4-(cyclobutylmethyl)thiazole

To a solution of 4-(cyclobutylmethyl)thiazol-2-amine (122 mg, 0.726mmol, Example 15, step a) and isoamyl nitrite (92 mg, 0.79 mmol) inacetonitrile (8 mL) was added CuBr (124 mg, 0.864 mmol). The mixture wasstirred at 70° C. for 1 h and then water was added. The mixture wasextracted with EtOAc three times and the combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by FCC on silica gel(PE/EtOAc=20:1) to give the title compound as a brown oil.

Example 15 Step c Methyl 3-(3-bromophenyl)-2,2-dimethylpropanoate

To a solution of methyl isobutyrate (129 mg, 1.26 mmol) in dry THF (10mL) was added LDA (0.92 mL, 2.5 M solution inTHF/n-heptane/ethylbenzene, 2.3 mmol) under Ar at −78° C., and themixture was stirred at this temperature for 1 h.1-Bromo-3-(bromomethyl)benzene (286 mg, 1.15 mmol) was added slowly andthe solution was stirred at −78° C. for 4 h. The mixture was quenchedwith aqueous NH₄Cl solution, allowed to warm to rt, and extracted withEtOAc three times. The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness togive the title compound as a yellow solid.

Example 15 Step d Methyl2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

To a solution of methyl 3-(3-bromophenyl)-2,2-dimethylpropanoate (132mg, 487 μmol, Example 15, step c), bis(pinacolato)diboron (167 mg, 658μmol) and KOAc (96 mg, 0.98 mmol) in dioxane (4 mL) was addedPd(dppf)Cl₂ (15 mg) under Ar. The mixture was stirred at 80° C.overnight. Water was added, and the mixture was extracted with EtOActhree times. The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated to dryness. The yellowresidue was purified by FCC on silica gel (PE/EtOAc=20:1) to give thetitle compound as a colorless solid.

Example 15 Step e Methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)phenyl)-2,2-dimethylpropanoate

To a solution of 2-bromo-4-(cyclobutylmethyl)thiazole (56 mg, 0.24 mmol,Example 15, step b), methyl2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(84 mg, 0.26 mmol, Example 15, step d) and Na₂CO₃ (64 mg, 0.60 mmol) indioxane/water (3 mL, 10:1 v/v) was added Pd(PPh₃)₄ (6 mg, 0.0052 mmol)under Ar. The mixture was stirred at 100° C. overnight. The reactionmixture was allowed to cool before water was added, and the resultingmixture was extracted with EtOAc three times. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ and filtered.The filtrate was concentrated to dryness, and the yellow residue waspurified by FCC on silica gel (PE/EtOAc=8:1) to give the title compoundas a colorless solid.

Example 15(S)-3-(3-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)phenyl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a methyl3-(3-(4-(cyclobutylmethyl)thiazol-2-yl)phenyl)-2,2-dimethylpropanoate(Example 15, step e) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 12.40 (s, 1H), 9.22 (d, J=9.2 Hz, 1H), 8.09 (d, J=9.2Hz, 1H), 7.81-7.45 (m, 3H), 7.43 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.8 Hz,1H), 4.21-4.16 (m, 1H), 2.89 (s, 2H), 2.67-2.62 (m, 3H), 1.97-1.90 (m,2H), 1.77-1.62 (m, 2H), 1.58-1.51 (m, 2H), 1.26 (d, J=6.8 Hz, 3H), 1.12(s, 6H). MS (ESI): m/z 649.1 [M+H]⁺.

Example 16(S)-3-(6-(4-(Cyclobutylmethyl)-5-(8-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-5-yl)thiazol-2-yl)pyridin-2-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a ethyl3-(6-(4-(cyclobutylmethyl)thiazol-2-yl)pyridin-2-yl)-2,2-dimethylpropanoate(Intermediate 14) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (5)-5-bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-8-sulfonamide(Intermediate 4/16) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 10.12 (s, 1H), 9.30 (br s, 1H), 8.72 (d, J=5.6 Hz, 1H),8.35 (d, J=7.6 Hz, 1H), 8.02-8.00 (m, 2H), 7.91 (t, J=7.6 Hz, 1H), 7.70(d, J=6.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 4.18-4.15 (m, 1H), 3.02 (s,2H), 2.58 (s, 3H), 1.88-1.82 (m, 2H), 1.70-1.53 (m, 2H), 1.44-1.38 (m,2H), 1.15 (s, 6H), 1.09 (d, J=7.2 Hz, 3H). MS (ESI): m/z 633.3 [M+H]⁺.

Example 17(S)-3-(6-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)thiazol-2-yl)pyrimidin-4-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a ethyl3-(6-(4-(cyclobutylmethyl)thiazol-2-yl)pyrimidin-4-yl)-2,2-dimethylpropanoate(Intermediate 15) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide(Intermediate 4/2) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 12.34 (s, 1H), 9.22 (d, J=9.2 Hz, 1H), 9.14 (s, 1H),8.11 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 4.22-4.16(m, 1H), 3.11 (s, 2H), 2.70-2.60 (m, 3H), 1.97-1.90 (m, 2H), 1.75-1.65(m, 2H), 1.57-1.50 (m, 2H), 1.26 (d, J=6.8 Hz, 3H), 1.19 (s, 6H). MS(ESI): m/z 651.1 [M+H]⁺.

Example 17/1(S)-3-(6-(4-(Cyclobutylmethyl)-5-(8-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)isoquinolin-5-yl)thiazol-2-yl)pyrimidin-4-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 3, using in step a ethyl3-(6-(4-(cyclobutylmethyl)thiazol-2-yl)pyrimidin-4-yl)-2,2-dimethylpropanoate(Intermediate 15) in place of methyl3-(5-(4-(cyclobutylmethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoateand (5)-5-bromo-N-(1,1,1-trifluoropropan-2-yl)isoquinoline-8-sulfonamide(Intermediate 4/16) in place of4-bromo-N-(tert-butyl)-2,3-dichlorobenzenesulfonamide. ¹H NMR (400 MHz,CDCl₃): δ ppm 10.31 (s, 1H), 9.14 (s, 1H), 8.72 (d, J=6.0 Hz, 1H), 8.43(d, J=7.4 Hz, 1H), 8.08-8.03 (m, 2H), 7.84 (d, J=7.4 Hz, 1H), 7.72 (d,J=6.0 Hz, 1H), 4.04 (s, 1H), 3.22 (s, 2H), 2.68-2.61 (m, 3H), 1.94-1.90(m, 2H), 1.77-1.61 (m, 2H), 1.47-1.40 (m, 2H), 1.37-1.31 (m, 9H). MS(ESI): m/z 634.1 [M+H]⁺.

Example 18(S)-3-(4-(Cyclobutylmethyl)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-[2,5′-bithiazol]-2′-yl)-2,2-dimethylpropanoicacid

The title compound was prepared as described for the synthesis ofExample 15, using in step e ethyl2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)propanoate(Intermediate 12) in place of methyl2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate.¹H NMR (500 MHz, CDCl₃): δ ppm 8.10-8.06 (m, 2H), 7.44 (d, J=8.5 Hz,1H), 5.40 (d, J=9.5 Hz, 1H), 4.11-4.07 (m, 1H), 3.35 (s, 2H), 2.66-2.60(m, 3H), 1.98-1.95 (m, 2H), 1.81-1.69 (m, 2H), 1.55-1.51 (m, 2H), 1.42(d, J=7.0 Hz, 3H), 1.36 (s, 6H). MS (ESI): m/z 656.1 [M+H]⁺.

The compounds of Example 19-24 can be made according to the proceduresdescribed below.

Example 19(S)-2-(4-(4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-2-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)thiazol-5-yl)-3-(difluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound can be prepared as described in Example 6, using instep a2-(4-bromo-3-(difluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 11) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamideand in step c (S)-4,4-difluoro-2-methylpyrrolidine hydrochloride(Intermediate 16, salt can be converted to the free base with TEA priorto the coupling) in place of 3,3-difluoropiperidine.

Example 20 Step a(S)-4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(2-(difluoromethyl)-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazole-2-carbohydrazide

The title compound can be prepared as described in Example 6, steps a-d,using in step a2-(4-bromo-3-(difluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 11) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamideand in step c (S)-4,4-difluoro-2-methylpyrrolidine hydrochloride(Intermediate 16, salt can be converted to the free base with TEA priorto the coupling) in place of 3,3-difluoropiperidine.

Example 20(S)-3-(5-(4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(2-(difluoromethyl)-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound can be prepared as described in Example 7, using instep a(S)-4-((4,4-difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(2-(difluoromethyl)-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazole-2-carbohydrazide(Example 20, step a) in place of(S)-2,3-dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(hydrazinecarbonyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide.

Example 21(S)-3-(3-(4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(2-(difluoromethyl)-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound can be prepared as described in Example 12, using instep a2-(4-bromo-3-(difluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Intermediate 11) in place of(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamideand in step c (S)-4,4-difluoro-2-methylpyrrolidine hydrochloride(Intermediate 16, salt can be converted to the free base with TEA priorto the coupling) in place of 3,3-difluoropiperidine.

Example 22 Step a2-(4-Bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound can be prepared as described in Intermediate 11,using in step b 1-bromo-4-iodo-2-methylbenzene in place of1-bromo-2-(difluoromethyl)-4-iodobenzene.

Example 22(S)-2-(4-(4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-2-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)thiazol-5-yl)-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound can be prepared as described in Example 6, using instep a 2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Example 22, step a) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamideand in step c (S)-4,4-difluoro-2-methylpyrrolidine hydrochloride(Intermediate 16, salt can be converted to the free base with TEA priorto the coupling) in place of 3,3-difluoropiperidine.

Example 23 Step a(S)-4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)thiazole-2-carbohydrazide

The title compound can be prepared as described in Example 6, steps a-d,using in step a2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Example22, step a) in place of(S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamideand in step c (S)-4,4-difluoro-2-methylpyrrolidine hydrochloride(Intermediate 16, salt can be converted to the free base with TEA priorto the coupling) in place of 3,3-difluoropiperidine.

Example 23(S)-3-(5-(4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoicacid

The title compound can be prepared as described in Example 7, using instep a(S)-4-((4,4-difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(4(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)thiazole-2-carbohydrazide(Example 23, step a) in place of(S)-2,3-dichloro-4-(4-((3,3-difluoropiperidin-1-yl)methyl)-2-(hydrazinecarbonyl)thiazol-5-yl)-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamide.

Example 24(S)-3-(3-(4-((4,4-Difluoro-2-methylpyrrolidin-1-yl)methyl)-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)thiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylpropanoicacid

The title compound can be prepared as described in Example 12, using instep a 2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(Example 22, step a) in place of(S)-4-bromo-3-(difluoromethyl)-2-fluoro-N-(1,1,1-trifluorobutan-2-yl)benzenesulfonamideand in step c (5)-4,4-difluoro-2-methylpyrrolidine hydrochloride(Intermediate 16, salt can be converted to the free base with TEA priorto the coupling) in place of 3,3-difluoropiperidine.

In Vitro Biological Data ThermoFluor® Assay

ThermoFluor® is a fluorescence based assay that estimates ligand bindingaffinities by measuring the effect of a ligand on protein thermalstability (Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D.,Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B.A., Lane, P., and Salemme, F. R. (2001) High-density miniaturizedthermal shift assays as a general strategy for drug discovery. J BiomolScreen 6, 429-40, and Matulis, D., Kranz, J. K., Salemme, F. R., andTodd, M. J. (2005) Thermodynamic stability of carbonic anhydrase:measurements of binding affinity and stoichiometry using ThermoFluor.Biochemistry 44, 5258-66). This approach is applicable to a wide varietyof systems, and rigorous in theoretical interpretation throughquantitation of equilibrium binding constants (K_(D)).

In a ThermoFluor® experiment where protein stability is monitored as thetemperature is steadily increased, an equilibrium binding ligand causesthe midpoint of an unfolding transition (T_(m)) to occur at a highertemperature. The shift in the melting point described as a ΔT_(m) isproportional to the concentration and affinity of the ligand. Thecompound potency may be compared as a rank order of either ΔT_(m) valuesat a single compound concentration or in terms of K_(D) values,estimated from concentration response curves.

RORγt ThermoFluor® Assay Construct

For the RORγt construct used in the ThermoFluor® assay, numbering forthe nucleotide sequences was based on the reference sequence for humanRORγt, transcript variant 2, NCBI Accession: NM 001001523.1 (SEQ IDNO:1). Nucleotides 850-1635 (SEQ ID NO:2) coding for the wild type humanRORγt ligand binding domain (RORγt LBD) were cloned into the pHIS1vector, a modified pET E. coli expression vector (Accelagen, San Diego),containing an in-frame N-terminal His-tag and a TurboTEV proteasecleavage site (ENLYFQG, SEQ ID NO:3) upstream of the cloned insertsequence. The amino acid sequence for the RORγt construct used in theThermofluor assay is shown as SEQ ID NO:4.

ThermoFluor® experiments were carried out using instruments owned byJanssen Research and Discovery, L.L.C. through its acquisition of3-Dimensional Pharmaceuticals, Inc. 1,8-ANS (Invitrogen) was used as afluorescent dye. Protein and compound solutions are dispensed into black384-well polypropylene PCR microplates (Abgene) and overlayed withsilicone oil (1 μL, Fluka, type DC 200) to prevent evaporation.

Bar-coded assay plates are robotically loaded onto a thermostaticallycontrolled PCR-type thermal block and then heated at a typical ramp-rateof 1° C./min for all experiments. Fluorescence was measured bycontinuous illumination with UV light (Hamamatsu LC6) supplied via fiberoptic and filtered through a band-pass filter (380-400 nm; >6 ODcutoff). Fluorescence emission of the entire 384-well plate was detectedby measuring light intensity using a CCD camera (Sensys, RoperScientific) filtered to detect 500±25 nm, resulting in simultaneous andindependent readings of all 384 wells. Images were collected at eachtemperature, and the sum of the pixel intensity in a given area of theassay plate was recorded versus temperature. Reference wells containedRORγt without compounds, and the assay conditions were as follows:

-   -   0.065 mg/mL RORγt    -   60 μM 1,8-ANS    -   100 mM Hepes, pH 7.0    -   10 mM NaCl    -   2.5 mM GSH    -   0.002% Tween-20

Project compounds were arranged in a pre-dosed mother plate (GreinerBio-one) wherein compounds are serially diluted in 100% DMSO by 1:2 froma high concentration of 10 mM over 12 columns within a series (column 12is a reference well containing DMSO, no compound). The compounds wererobotically dispensed directly into assay plates (1×=46 nL) using aHummingbird capillary liquid handling instrument (Digilab). Followingcompound dispense, protein and dye in buffer was added to achieve thefinal assay volume of 3 μL, followed by 1 μL of silicone oil.

The binding affinity was estimated as described previously (Matulis, D.,Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005) Thermodynamicstability of carbonic anhydrase: measurements of binding affinity andstoichiometry using ThermoFluor®. Biochemistry 44, 5258-66) using thefollowing thermodynamic parameters of protein unfolding:

Reference RORγt T_(m): 47.8° C.

ΔH_((Tm))=115 kcal/mol

ΔC_(p(Tm))=3 kcal/mol

Cell Based Biological Data

RORγt (full-length human) Reporter Assay:

Three similar reporter assay protocols, shown below, have been used totest the functional activity of RORγt modulatory compounds ontranscriptional activation driven by full-length human RORγt. All threeprovide similar data and can be used interchangeably.

Conditions A

Cells used in this assay were transiently co-transfected with threedifferent plasmids, one expressing the GAL4-DNA binding domain(DBD)-RORγt fusion protein under control of a CMV promoter(NH2-Gal4-DBD:RORC—COOH in pCMV-BD, Stratagene #211342), and tworeporter plasmids—the firefly luciferase reporter under control of aGAL4 promoter (pFR-Luc 2×GAL4) and Renilla luciferase reporter undercontrol of CMV promoter (pRL-CMV, Promega #E2261). The full-lengthcoding sequence was used for human RORγt, i.e., nucleotides 142-1635 ofhuman RORγt, transcript variant 2, NCBI Accession: NM 001001523.1 (SEQID NO:1). HEK293T cells were plated at 35000 per well in 96-well platein medium of MEM with 8.6% FBS. After 18-22 hours incubation, thetransfection was carried out by using a PEI solution with 170.5 ng totalDNA/well (50 ng pCMV-BD-ROR plus 20 ng of pFR-Luc reporter and 0.5 ng ofpRL-CMV reporter plus 100 ng Carrier DNA (Clontech #630440) for eachwell). 4-6 hours after transfection, cells were treated with compoundsfor overnight in the medium with final concentration of FBS 1.1% andDMSO 0.1%. After overnight (16 to 20 hours) incubation, media wereremoved and cells were lysed with 20 μL 1× Passive Lysis Buffer(Promega) for 10-15 minutes. Luminescence was measured using a BMGLUMIstar OPTIMA plate reader, after addition of 75 μL/well fireflyluciferase buffer, followed by 75 μL/well Renilla luciferase buffer. Tocalculate the effect of compounds on RORγt activity, firefly values werenormalized against values of DMSO only and values of reference compoundat saturating concentration, then further normalized against Renillasignals. IC50s were generated by plotting final Renilla normalized dataagainst compound concentration and percent inhibition was calculatedagainst DMSO control.

Conditions B

Cells used in this assay were transiently co-transfected with threedifferent plasmids, one expressing the GAL4-DNA binding domain(DBD)-RORγt fusion protein under control of a CMV promoter(NH2-Gal4-DBD:RORC—COOH in pCMV-BD, Stratagene #211342), and tworeporter plasmids—the firefly luciferase reporter under control of aGAL4 promoter (pFR-Luc 2×GAL4) and Renilla luciferase reporter undercontrol of CMV promoter (pRL-CMV, Promega #E2261). The full-lengthcoding sequence was used for human RORγt, i.e., nucleotides 142-1635 ofhuman RORγt, transcript variant 2, NCBI Accession: NM 001001523.1 (SEQID NO:1). HEK293T cells were plated at 35,000 per well in 96-well platein medium of DMEM with 10% FBS. After 18-22 hours incubation, thetransfection was carried out by using a PEI solution with 170.5 ng totalDNA/well (50 ng pCMV-BD-ROR plus 20 ng of pFR-Luc reporter and 0.5 ng ofpRL-CMV reporter plus 100 ng Carrier DNA (Clontech #630440) for eachwell). 4-6 hours after transfection, cells were treated with compoundsfor overnight in the medium with final concentration of FBS 1.3% andDMSO 0.1%. After overnight (16 to 20 hours) incubation, media wereremoved and cells were lysed with 50 μL Glo Lysis Buffer (Promega) for10-15 minutes followed by 10 minute incubation with 50 μL Dual Gloreagent (Promega) at room temperature. Firefly luciferase luminescencewas measured using a BMG Pherastar plate reader. To each well, 50 μLStop and Glo reagent was added and incubated for 10 minutes at roomtemperature. Renilla luminescence was measured using a BMG Pherastarplate reader. To calculate the effect of compounds on RORγt activity,firefly values were normalized against values of DMSO only and values ofreference compound at saturating concentration, then further normalizedagainst Renilla signals. IC50s were generated by plotting final Renillanormalized data against compound concentration and percent inhibitionwas calculated against DMSO control.

Conditions C

Cells used in this assay were transiently co-transfected with threedifferent plasmids, one expressing the GAL4-DNA binding domain(DBD)-RORγt fusion protein under control of a CMV promoter(NH2-Gal4-DBD:RORC—COOH in pCMV-BD, Stratagene #211342), and tworeporter plasmids—the firefly luciferase reporter under control of aGAL4 promoter (pFR-Luc 2×GAL4) and Renilla luciferase reporter undercontrol of CMV promoter (pRL-CMV, Promega #E2261). The full-lengthcoding sequence was used for human RORγt, i.e., nucleotides 142-1635 ofhuman RORγt, transcript variant 2, NCBI Accession: NM 001001523.1 (SEQID NO:1). HEK293T cells were plated at 8750 cells per well in 384-wellplate in medium of DMEM with 10% FBS. After 18-22 hours incubation, thetransfection was carried out by using a PEI solution with 42.6 ng totalDNA/well (12.5 ng pCMV-BD-ROR plus 5 ng of pFR-Luc reporter and 0.125 ngof pRL-CMV reporter plus 25 ng Carrier DNA (Clontech #630440) for eachwell). 4-6 hours after transfection, cells were treated with compoundsfor overnight in the medium with final concentration of FBS 1.3% andDMSO 0.1%. After overnight (16 to 20 hours) incubation, media wereremoved and cells were lysed with 20 μL Glo Lysis Buffer (Promega) for10-15 minutes followed by 10 minute incubation with 20 μL Dual Gloreagent (Promega) at room temperature. Firefly luciferase luminescencewas measured using a BMG Pherastar plate reader. To each well, 20 μLStop and Glo reagent was added and incubated for 10 minutes at roomtemperature. Renilla luminescence was measured using a BMG Pherastarplate reader. To calculate the effect of compounds on RORγt activity,firefly values were normalized against values of DMSO only and values ofreference compound at saturating concentration, then further normalizedagainst Renilla signals. IC50s were generated by plotting final Renillanormalized data against compound concentration and percent inhibitionwas calculated against DMSO control.

Human Th17 Assay

The human Th17 assay tests the effect of RORγt modulatory compounds onIL-17 production by CD4 T cells under conditions which favor Th17differentiation. Total CD4⁺ T cells were isolated from the peripheralblood mononuclear cells (PBMC) of healthy donors using a CD4⁺ T cellisolation kit II, following the manufacturer's instructions (MiltenyiBiotec). Cells were resuspended in a medium of RPMI-1640 supplementedwith 10% fetal bovine serum, penicillin, streptomycin, glutamate, andβ-mercaptoethanol and were added to 96-well plates at 1.5×10⁵ per 100 μLper well. 50 μL of compound at titrated concentrations in DMSO wereadded into each well at final DMSO concentration at 0.2%. Cells wereincubated for 1 hour, then 50 μL of Th17 cell differentiation medium wasadded to each well. The final concentrations of antibodies and cytokines(R&D Systems) in differentiation medium were: 3×10⁶/mL anti-CD3/CD28beads (prepared using human T cell activation/expansion kit, MiltenyiBiotec), 10 μg/mL anti-IL4, 10 μg/mL anti-IFNγ, 10 ng/mL IL1β, 10 ng/mLIL23, 50 ng/mL IL6, 3 ng/mL TGFβ and 20 U/mL IL2. Cells were cultured at37° C. and 5% CO₂ for 3 days. Supernatants were collected and theaccumulated IL-17 in culture was measured by using MULTI-SPOT® CytokinePlate following manufacture's instruction (Meso Scale Discovery). Theplate was read using Sector Imager 6000, and IL-17 concentration wasextrapolated from the standard curve. The IC50s were determined byGraphPad.

TABLE 1 RORγt RORγt RORγt RORγt (FL) Reporter (FL) Reporter (FL)Reporter ThermoFluor ® (FL) Reporter Assay A, % Assay B or Assay B or C,% Human Th17 Example Assay, Kd Assay A, IC₅₀ inhibition C, IC₅₀inhibition Assay, IC₅₀ # (μM) (μM) @ 6 μM (μM) @ 6 μM (μM)  1 0.067 NDND ND ND ND 1/1  0.00082 ND ND ND ND  0.0078  2 0.012 ND ND ND ND 0.037 3 0.0033 0.010 105* ND ND ND 3/1  0.00025 0.0034   107***** ND ND ND3/2  0.00055 ND ND ND ND ND 3/3  0.00035 0.0052 106* ND ND ND 3/4 0.000050 0.0016  103*** ND ND ND 3/5  0.0032 0.021 100* ND ND ND 3/6 0.15 0.48  72* ND ND ND 3/7  0.093 0.089  94* ND ND ND 3/8a ~0.00300.015  101** ND ND ND 3/8b 0.14 0.17  65** ND ND ND 3/9  0.00036 0.0043105* ND ND ND 3/10 0.0054 0.037 106* ND ND ND 3/11 0.0036 0.025 105* NDND ND 3/12 0.0087 0.047 103* ND ND ND 3/13 0.0020 0.0090 106  ND ND ND3/14 0.022 0.061 105* ND ND ND 3/15 0.00033 0.019 106* ND ND ND 3/160.011 0.66 102  ND ND ND 3/17 0.0075 0.84 102  ND ND 0.75  3/18 0.00540.015 103* ND ND ND 3/19 0.0065 0.015 101* ND ND ND 3/20 0.000020 0.0030 102** ND ND ND 3/21 0.00020 0.011   99**** ND ND ND 3/22 0.00033 0.094105* ND ND ND 3/23 0.000045 0.014 105* ND ND ND 3/24 0.000036 0.0080105* ND ND ND 3/25 0.000058 0.0026 105* ND ND ND 3/26 0.000025 0.0036 106** ND ND ND 3/27 0.00047 0.058 107  ND ND ND 3/28 0.0033 0.50 106 ND ND ND 3/29 0.000083 0.0029  102** ND ND ND 3/30 0.00028 0.0036 105*ND ND ND 3/31 0.00096 0.022 108* ND ND ND 3/32 0.000044 0.0070 109  NDND ND 3/33 0.000070 0.0080 103* ND ND ND 3/34 0.018 0.12  94* ND ND ND3/35 0.0056 0.011 100* ND ND ND 3/36 0.0011 0.0046  99** ND ND ND 3/370.0040 0.045 104* ND ND ND 3/38 0.000038 0.0032 104* ND ND ND 3/390.00071 0.039 109  ND ND ND 3/40 0.000030 0.0080 104* ND ND ND 3/410.000020 0.0045  104** ND ND ND 3/42 0.00012 0.0090 103* ND ND ND 3/430.0013 ND ND 0.076 103 ND  4 0.0023 0.025 104  ND ND ND 4/1  0.000270.013 109  0.011 108 0.034 4/2  0.000040 0.0050  98* ND ND ND  5 0.00430.027 106* ND ND ND  6 0.0012 0.0060  104** ND ND ND  7 0.00032 0.021105  ND ND ND  8 0.00020 0.13 108  ND ND 0.082 8/1  0.00012 0.089 107 ND ND ND 8/2  0.0011 0.037 103* ND ND ND 8/3  0.0016 0.12 79 ND ND 0.093 9 0.014 0.016  103** ND ND ND 10 0.18 ND ND ND ND ND 11 0.00039 0.0036 99** ND ND ND 11/1  0.00062 0.0090  99** ND ND ND 11/2  0.00012 0.0090107* ND ND ND 11/3  0.000080 0.010 106* ND ND ND 11/4  0.000060 0.0080   99****** ND ND ND 11/5  0.00021 0.016 106* ND ND ND 11/6  0.000140.0044 105* ND ND ND 11/7  0.00027 0.0070 102* ND ND ND 11/8  0.000350.013 105  ND ND ND 11/9  0.00015 0.0042  102** ND ND ND 11/10  0.000230.0032 104* ND ND ND 11/11  0.000024 0.0043 106* ND ND ND 12 0.000120.014 105  ND ND ND 12/1  0.000050 0.0033 107* ND ND ND 12/2  0.0000190.0048 107* ND ND ND 12/3  0.000063 0.014 103* ND ND ND 12/4  0.00180.31 98 ND ND 0.26  12/5  0.00033 0.026 107  ND ND ND 12/6  0.0016 0.029 95* ND ND ND 12/7  0.00029 0.49 106  ND ND ND 13 0.44 ND ND ND ND ND 140.0027 0.0080  97** ND ND ND 15 0.00062 0.0042  100** ND ND ND 160.00017 0.0049  103** ND ND ND 17 0.0015 0.015 103* ND ND ND 17/1  0.0230.19 100* ND ND ND 18 0.00046 0.011 108* ND ND ND All data shown inTable 1 is either the value of one data point or the average of morethan one data point. ND: value not determined. *% inhibition is shown at2 μM compound concentration, **% inhibition is shown at 0.67 μM compoundconcentration, ***% inhibition is shown at 0.5 μM compoundconcentration, ****% inhibition is shown at 0.22 μM compoundconcentration, *****% inhibition is shown at 0.19 μM compoundconcentration, ******% inhibition is shown at 0.17 μM compoundconcentration.

All data shown in Table 1 is either the value of one data point or theaverage of more than one data point.

ND: value not determined. *% inhibition is shown at 2 μM compoundconcentration, **% inhibition is shown at 0.67 μM compoundconcentration, ***% inhibition is shown at 0.5 μM compoundconcentration, ****% inhibition is shown at 0.22 μM compoundconcentration, *****% inhibition is shown at 0.19 μM compoundconcentration, ******% inhibition is shown at 0.17 μM compoundconcentration.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

All documents cited herein are incorporated by reference.

We claim:
 1. A compound of Formula I:

wherein

is phenyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazyl; R¹ is H, Cl,OCF₃, C₍₁₋₄₎alkyl, —CN, F, OC₍₁₋₄₎alkyl, OCHF₂, Br, I, or cyclopropyl;wherein said C₍₁₋₄₎alkyl is optionally substituted with up to sixfluorine atoms; R² is H, F, Cl, —CN, OC₍₁₋₄₎alkyl, OCHF₂, OCF₃,cyclopropyl, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionallysubstituted with up to five fluorine atoms, and said cyclopropyl isoptionally substituted with OH, CH₃, CF₃, —CN, and up to five fluorineatoms; or R¹ and R² may be taken together with their attached ring A toform a fused ring system selected from the group consisting ofnaphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, quinolinyl,2,3-dihydro-1H-indenyl, chromanyl, isochromanyl, and naphthyridinyl;wherein said naphthalenyl, isoquinolinyl, tetrahydronaphthalenyl,quinolinyl, 2,3-dihydro-1H-indenyl, chromanyl, isochromanyl, andnaphthyridinyl are optionally substituted up to three times with F,C₍₁₋₃₎alkyl, or OC₍₁₋₃₎alkyl; wherein each substituent is selectedindependently; wherein said OC₍₁₋₃₎alkyl and C₍₁₋₃₎ alkyl is optionallysubstituted with up to five fluorine atoms; provided that R² may not beH if R¹ is H; R³ is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl,isoxazolyl, phenyl, oxazolyl, triazolyl, tetrazolyl,1,2,4-oxadiazol-5(4H)-on-3-yl, pyridyl, pyrimidyl, pyridazyl, pyrazyl,imidazolyl, pyrrolyl, or furanyl; wherein said oxadiazolyl, thiazolyl,thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl,pyridyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, pyrrolyl, or furanylis optionally substituted with R⁶, and further optionally substitutedwith one substituent selected from the group consisting of F, CH₃, andCF₃; R⁶ is

C₍₁₋₆₎ alkyl, C(O)NH₂, —CN, C₍₃₋₆₎cycloalkyl, NH₂, NH(C₍₁₋₆₎alkyl),N(C₍₁₋₆₎alkyl)₂, NHCO(C₍₁₋₆₎alkyl), N(C₍₁₋₆₎alkyl)CO(C₍₁₋₆₎alkyl),NHSO₂(C₍₁₋₆₎alkyl), N(C₍₁₋₆₎alkyl)SO₂(C₍₁₋₆₎alkyl), O(C₍₁₋₆₎alkyl),C(O)NH₂, CONH(C₍₁₋₆₎alkyl), CON(C₍₁₋₆₎alkyl)₂, SO₂NH₂,SO₂NH(C₍₁₋₆₎alkyl), SO₂NH(COC₍₁₋₆₎alkyl), or SO₂N(C₍₁₋₆₎alkyl)₂; whereinsaid C₍₁₋₆₎alkyl or C₍₃₋₆₎cycloalkyl is optionally independentlysubstituted with up to six fluorine atoms, CO₂H, OH, —CN, C(O)NH₂, NH₂,OCH₃, OCHF₂, OCF₃, —(CX₂)_(m)—, Or N(CH₃)₂; wherein m is 2, 3, 4, or 5;X is H, or F; wherein each occurrence of X in a single molecule isindependently defined; R⁴ is H, C₍₃₋₈₎cycloalkyl, C₍₃₋₈₎alkyl,OC₍₁₋₈₎alkyl, phenyl, pyridyl, CH₂SO₂C₍₁₋₃₎alkyl, NA¹A²,CH₂O—C₍₃₋₈₎alkyl, O—C₍₃₋₈₎cycloalkyl, tetrahydrofuranyl,tetrahydropyranyl, thiadiazolyl, oxadiazolyl, isoxadiazolyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl, pyrimidyl, pyridazyl, pyrazyl,imidazolyl, pyrrolyl, or furanyl, wherein said C₍₃₋₈₎alkyl andO—C₍₃₋₈₎alkyl are optionally substituted with 1 to 4 substituentsindependently selected from F, Cl, OH, OCH₃, OCHF₂, OCF₃, and —CN; andsaid C₍₃₋₈₎cycloalkyl, O—C₍₃₋₈₎cycloalkyl, tetrahydrofuranyl,tetrahydropyranyl, phenyl, thiadiazolyl, oxadiazolyl, isoxadiazolyl,oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,pyridazyl, pyrazyl, imidazolyl, pyrrolyl, and furanyl are optionallysubstituted with 1 to 4 substituents independently selected from thegroup consisting of F, Cl, CH₃, CHF₂, CF₃, OH, OCH₃, OCHF₂, OCF₃, and—CN; A¹ is H, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl is optionallysubstituted with up to six fluorine atoms, Cl, —CN, OCH₃, OCHF₂, orOCF₃; A² is C₍₁₋₆₎alkyl, C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl,

CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, or CH₂—CCH; wherein said C₍₁₋₆₎alkyl, andsaid C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl are optionally substituted with up tosix fluorine atoms, Cl, —CN, OCH₃, OCHF₂, or OCF₃; or A¹ and A² may betaken together with their attached nitrogen to form a ring selected fromthe group consisting of: thiomorpholinyl, piperidinyl, pyrrolidinyl,piperazinyl, morpholinyl, azetidinyl, and aziridinyl; wherein saidpiperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, azetidinyl, andaziridinyl are optionally substituted with CF₃, CHF₂, CH₂F, CH₂CH₂F,C₍₁₋₂₎alkyl, C₍₃₋₆₎cycloalkyl, —CN, OH, CH₂OH, F, Cl, OCH₃, OCHF₂, OCF₃,—(CX₂)_(n)O(CX₂)_(n)—, or —(CX₂)_(n)— and up to three additionalsubstituents selected from the group consisting of CH₃, and F; wherein nis independently 0, 1, 2, 3, or 4; X is H, or F; wherein each occurrenceof X in a single molecule is independently defined; R⁵ is SO₂NA³A⁴,CONA³A⁴, NA³A⁴, or C₍₁₋₆₎alkyl; wherein said C₍₁₋₆₎alkyl is optionallysubstituted with OH, Cl, —CN, OCH₃, OCHF₂, OCF₃, NA³A⁴, or cyclopropyl,and up to six fluorine atoms; A³ is H, or C₍₁₋₄₎alkyl; wherein saidC₍₁₋₄₎alkyl is optionally substituted with OH, Cl, —CN, OCH₃, OCHF₂, orOCF₃; and up to six fluorine atoms; A⁴ is C₍₁₋₆₎alkyl, C₍₃₋₆₎cycloalkyl,or C₍₃₋₆₎heterocycloalkyl; wherein said C₍₁₋₆₎alkyl is optionallysubstituted with cyclopropyl, morpholinyl, OH, OCH₃, C(O)NH₂, Cl, —CN,OCHF₂, OCF₃ and additionally substituted with up to three fluorineatoms; and wherein said C₍₃₋₆₎cycloalkyl, and C₍₃₋₆₎heterocycloalkyl areoptionally substituted with CF₃, CH₃, —CN, C(O)NH₂, and up to threefluorine atoms; or A³ and A⁴ can be taken together with their attachednitrogen to form a ring selected from the group consisting ofazetidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, andaziridinyl wherein said azetidinyl, piperidinyl, morpholinyl,piperazinyl pyrrolidinyl, and aziridinyl are optionally substituted withup to four groups selected from the group consisting of CF₃, OH, CH₃,CH₂F, and CHF₂; and further optionally substituted with up to sixfluorine atoms; R⁷ is H, F, OH, OCH₃, CH₃, CHF₂, CH₂F, or CF₃; R⁸ is H,or F; or if R⁴ is H, then R⁷ and R⁸ may be taken together to form aC₍₃₋₆₎cycloalkyl ring; and pharmaceutically acceptable salts thereof. 2.The compound of claim 1, wherein:

Z is N, or CH; R¹ is H, Cl, OCF₃, C₍₁₋₃₎alkyl, —CN, F, OC₍₁₋₃₎alkyl,OCHF₂, Br, I, or cyclopropyl; wherein said C₍₁₋₃₎alkyl is optionallysubstituted with up to five fluorine atoms; R² is H, F, Cl, —CN, OCH₃,OCHF₂, OCF₃, cyclopropyl, or C₍₁₋₄₎alkyl; wherein said C₍₁₋₄₎alkyl isoptionally substituted with up to five fluorine atoms, and saidcyclopropyl is optionally substituted with OH, CH₃, CF₃, —CN, and up tofive fluorine atoms; or R¹ and R² may be taken together with theirattached ring A to form a fused ring system selected from the groupconsisting of naphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, andquinolinyl, wherein said naphthalenyl, isoquinolinyl,tetrahydronaphthalenyl, and quinolinyl are optionally substituted withF, CHF₂, CH₂F, CF₃, or CH₃; provided that R² may not be H if R¹ is H; R³is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, tetrazolyl, 1,2,4-oxadiazol-5(4H)-on-3-yl,pyridyl, pyrimidyl, pyridazyl, pyrazyl, imidazolyl, or pyrrolyl; whereinsaid oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl,phenyl, oxazolyl, triazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl,imidazolyl, or pyrrolyl is optionally substituted with R⁶; R⁶ is

C₍₁₋₄₎alkyl, C(O)NH₂, or —CN; wherein said C₍₁₋₄₎alkyl is optionallysubstituted with up to six fluorine atoms, CO₂H, OH, or —CN; R⁴ isC₍₃₋₆₎cycloalkyl, isopropyl, C(CH₃)₂OCH₃, OC₍₁₋₄₎alkyl, fluorophenyl,difluorophenyl, pyridyl, CH₂SO₂CH₃, or NA¹A², wherein saidC₍₃₋₆₎cycloalkyl is optionally substituted with OCH₃, two fluoro groupsor two methyl groups; A¹ is H, or C₍₁₋₃₎alkyl; wherein said C₍₁₋₃₎alkylis optionally substituted with up to five fluorine atoms, Cl, —CN, OCH₃,OCHF₂, or OCF₃; A² is C₍₁₋₄₎alkyl, C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl,CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, or CH₂—CCH; wherein said C₍₁₋₄₎alkyl, andsaid C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl are optionally substituted with up tothree fluorine atoms, Cl, —CN, OCH₃, OCHF₂, or OCF₃; or A¹ and A² may betaken together with their attached nitrogen to form a ring selected fromthe group consisting of:

thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, andmorpholinyl; wherein said piperidinyl, pyrrolidinyl, piperazinyl, andmorpholinyl are optionally substituted with CF₃, CH₂F, CH₂CH₂F,C₍₁₋₂₎alkyl, —CN, OH, CH₂OH, F, Cl, OCH₃, OCHF₂, or OCF₃, and up tothree additional substituents selected from the group consisting of CH₃,and F; R⁵ is SO₂NA³A⁴, C₍₁₋₆₎alkyl,

wherein said C₍₁₋₆₎alkyl is optionally substituted with OH, Cl, —CN,OCH₃, OCHF₂, OCF₃, or NA³A⁴; and up to six fluorine atoms; A⁴ isC₍₁₋₆₎alkyl, C₍₃₋₆₎cycloalkyl, oxetanyl, or tetrahydrofuranyl; whereinsaid C₍₁₋₆₎alkyl is optionally substituted with cyclopropyl,morpholinyl, OH, OCH₃, or C(O)NH₂, and additionally substituted with upto three fluorine atoms; and wherein said C₍₃₋₆₎cycloalkyl, oxetanyl,and tetrahydrofuranyl are optionally substituted with CF₃, CH₃, —CN, orC(O)NH₂; or A³ and A⁴ can be taken together with their attached nitrogento form a ring selected from the group consisting of azetidinyl,piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl wherein saidazetidinyl, piperidinyl, morpholinyl, and piperazinyl are optionallysubstituted with up to four groups selected from the group consisting ofCF₃, OH, and CH₃; and further optionally substituted with up to sixfluorine atoms; R⁷ is H, F, OH, or OCH₃; R⁸ is H; and pharmaceuticallyacceptable salts thereof.
 3. The compound of claim 2, wherein:

R¹ is H, Cl, OCF₃, C₍₁₋₃₎alkyl, —CN, F, OC₍₁₋₃₎alkyl, OCHF₂, orcyclopropyl, wherein said C₍₁₋₂₎alkyl is optionally substituted with upto five fluorine atoms; R² is CHF₂, CF₃, H, F, Cl, —CN,

or R¹ and R² may be taken together with their attached ring A to form afused ring system selected from the group consisting of naphthalenyl,isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl, wherein saidnaphthalenyl, isoquinolinyl, tetrahydronaphthalenyl, and quinolinyl areoptionally substituted with F, CHF₂, CH₂F, CF₃, or CH₃; provided that R²may not be H if R¹ is H; R³ is oxadiazolyl, thiazolyl, thiadiazolyl,isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, tetrazolyl,1,2,4-oxadiazol-5(4H)-on-3-yl, pyridyl, pyrimidyl, pyridazyl, orpyrazyl; wherein said oxadiazolyl, thiazolyl, thiadiazolyl,isoxadiazolyl, isoxazolyl, phenyl, oxazolyl, triazolyl, pyridyl,pyrimidyl, pyridazyl, or pyrazyl is optionally substituted with R⁶; R⁶is

C₍₁₋₂₎alkyl, CH₂C(CH₃)₂CO₂H, C₍₀₋₁₎alkylC(CH₃)₂OH, CH₂C(CH₃)₂CN,C(O)NH₂, or —CN; wherein said C₍₁₋₂₎alkyl is optionally substituted withup to five fluorine atoms; R⁴ is C₍₃₋₆₎cycloalkyl, isopropyl,C(CH₃)₂OCH₃, OC₍₁₋₄₎alkyl, fluorophenyl, difluorophenyl, pyridyl,CH₂SO₂CH₃, or NA¹A², wherein said C₍₃₋₆₎cycloalkyl is optionallysubstituted with OCH₃, two fluoro groups or two methyl groups; A¹ is H,or C₍₁₋₃₎alkyl; wherein said C₍₁₋₃₎alkyl is optionally substituted withup to five fluorine atoms; A² is C₍₁₋₄₎alkyl,C₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl, CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, CH₂—CCH, orCH₂CH₂—CN; wherein said C₍₁₋₄₎alkyl, and saidC₍₀₋₂₎alkyl-C₍₃₋₆₎cycloalkyl are optionally substituted with up to threefluorine atoms; or A¹ and A² may be taken together with their attachednitrogen to form a ring selected from the group consisting of:

thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, andmorpholinyl; wherein said piperidinyl, pyrrolidinyl, piperazinyl, andmorpholinyl are optionally substituted with CF₃, CH₂F, CH₂CH₂F,C₍₁₋₂₎alkyl, —CN, OH, CH₂OH, or F, and up to three additionalsubstituents selected from the group consisting of CH₃, and F; R⁵ isSO₂NA³A⁴, C₍₁₋₆₎alkyl,

wherein said C₍₁₋₆₎alkyl is optionally substituted with OH, OCH₃, or,NA³A⁴, and up to six fluorine atoms; A³ is H, or C₍₁₋₄₎alkyl; A⁴ isC₍₁₋₆₎alkyl, cyclopropyl, cyclobutyl, oxetanyl, or tetrahydrofuranyl;wherein said C₍₁₋₆₎alkyl is optionally substituted with cyclopropyl,morpholinyl, OH, OCH₃, or C(O)NH₂, and additionally substituted with upto three fluorine atoms; and wherein said cyclopropyl cyclobutyl,oxetanyl, and tetrahydrofuranyl are optionally substituted with CF₃,CH₃, —CN, or C(O)NH₂; or A³ and A⁴ can be taken together with theirattached nitrogen to form a ring selected from the group consisting ofaztetidinyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinylwherein said aztetidinyl, piperidinyl, morpholinyl, and piperazinyl areoptionally substituted with up to two groups selected from the groupconsisting of CF₃, OH, and CH₃; and further optionally substituted withup to three fluorine atoms; and pharmaceutically acceptable saltsthereof.
 4. The compound of claim 3, wherein:

R¹ is H, Cl, OCF₃, CF₃, CHF₂, C₍₁₋₃₎alkyl, —CN, F, OC₍₁₋₃₎alkyl, orOCHF₂; R² is CHF₂, CF₃, H, F, Cl,

or R¹ and R² may be taken together with their attached ring A to form afused ring system selected from the group consisting of naphthalenyl,isoquinolinyl, and tetrahydronaphthalenyl; provided that R² may not be Hif R¹ is H; R³ is oxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl,isoxazolyl, phenyl, oxazolyl, triazolyl, tetrazolyl,1,2,4-oxadiazol-5(4H)-on-3-yl, pyridyl, or pyrimidyl, wherein saidoxadiazolyl, thiazolyl, thiadiazolyl, isoxadiazolyl, isoxazolyl, phenyl,oxazolyl, triazolyl, pyridyl or pyrimidyl is optionally substituted withR⁶; R⁶ is

CH₃, CH₂C(CH₃)₂CO₂H, C₍₀₋₁₎oalkylC(CH₃)₂OH, CH₂C(CH₃)₂CN, or C(O)NH₂; R⁴is C₍₃₋₆₎cycloalkyl, isopropyl, C(CH₃)₂OCH₃, OCH(CH₃)₂, OC(CH₃)₃,fluorophenyl, difluorophenyl, or NA¹A², wherein said C₍₃₋₆₎cycloalkyl isoptionally substituted with OCH₃, two fluoro groups or two methylgroups; A¹ is H, C₍₁₋₃₎alkyl, or CH₂CH₂F; A² is C₍₂₋₄₎alkyl,CH₂-cyclopentyl, CH₂CH₂-cyclopropyl, C₍₃₋₄₎cycloalkyl,

CH₂—C₆H₄—C(O)NH₂, —C₆H₄—F, CH₂—CCH, or CH₂CH₂—CN; wherein saidC₍₃₋₄₎cycloalkyl is optionally substituted with one fluorine atom andsaid C₍₂₋₄₎alkyl is optionally substituted with up to three fluorineatoms; or A¹ and A² may be taken together with their attached nitrogento form a ring selected from the group consisting of:

thiomorpholinyl, piperidinyl, pyrrolidinyl, and morpholinyl; whereinsaid piperidinyl, and pyrrolidinyl are optionally substituted with CF₃,CH₂F, CH₂CH₂F, C₍₁₋₂₎alkyl, —CN, OH, or CH₂OH, and up to threeadditional substituents selected from the group consisting of CH₃, andF; R⁵ is SO₂NA³A⁴, C(CF₃)₂OH,

A³ is H, CH₃CH₂, or C(CH₃)₃; A⁴ is C₍₁₋₆₎alkyl,

C(CH₃)₂CH₂OCH₃, C(CH₃)₂CH₂OH, C(CH₃)₂CH₂-morpholinyl, C(CH₃)₂CH₂CH₂OH,C(CH₃)₂CH₂C(O)NH₂, or CH₂C(CH₃)₂OH; wherein said C₍₁₋₆₎alkyl isoptionally substituted with up to three fluorine atoms; or A³ and A⁴ canbe taken together with their attached nitrogen to form a ring selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 5. The compound of claim4, wherein: R¹ is H, Cl, OCF₃, CF₃, CHF₂, or F; R² is CHF₂, CF₃, H, F,Cl,

or R¹ and R² may be taken together with their attached ring A to form afused ring system selected from the group consisting of naphthalenyl,and isoquinolinyl; provided that R² may not be H if R¹ is H; R³ is

or phenyl, wherein said phenyl is optionally substituted with R⁶; R⁶ is

CH₃, CH₂C(CH₃)₂CO₂H, or C(CH₃)₂OH; R⁴ is C₍₄₋₆₎cycloalkyl, isopropyl,C(CH₃)₂OCH₃, OCH(CH₃)₂, difluoropiperidinyl, fluoropiperidinyl,fluorophenyl, or NA¹A², wherein said C₍₄₋₆₎cycloalkyl is optionallysubstituted with OCH₃, two fluoro groups or two methyl groups; andwherein A¹ and A² are taken together with their attached nitrogen toform a pyrrolidinyl ring, wherein said pyrrolidinyl ring is optionallysubstituted with CH₃, CH₂F, and up to three additional substituentsselected from the group consisting of CH₃, and F; R⁵ is SO₂NA³A⁴,C(CF₃)₂OH,

A³ is H; A⁴ is

or C(CH₃)₃; and pharmaceutically acceptable salts thereof.
 6. Thecompound of claim 5 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 7. The compound of claim4 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 8. A pharmaceuticalcomposition, comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 9. A pharmaceutical composition made by mixing acompound of claim 1 and a pharmaceutically acceptable carrier.
 10. Aprocess for making a pharmaceutical composition comprising mixing acompound of claim 1 and a pharmaceutically acceptable carrier.
 11. Amethod for treating or ameliorating a RORγt mediated inflammatorysyndrome, disorder or disease comprising administering to a subject inneed thereof an effective amount of a compound of claim
 1. 12. Themethod of claim 11, wherein the disease is selected from the groupconsisting of: rheumatoid arthritis, psoriasis, chronic obstructivepulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn'sdisease, neutrophilic asthma, steroid resistant asthma, multiplesclerosis, systemic lupus erythematosus, and ulcerative colitis.
 13. Themethod of claim 11, wherein the disease is psoriasis.
 14. The method ofclaim 11, wherein the disease is rheumatoid arthritis.
 15. The method ofclaim 11, wherein the disease is ulcerative colitis.
 16. The method ofclaim 11, wherein the disease is Crohn's disease.
 17. The method ofclaim 11, wherein the disease is multiple sclerosis.
 18. The method ofclaim 11, wherein the disease is neutrophilic asthma.
 19. The method ofclaim 11, wherein the disease is steroid resistant asthma.
 20. Themethod of claim 11, wherein the disease is psoriatic arthritis.
 21. Themethod of claim 11, wherein the disease is ankylosing spondylitis. 22.The method of claim 11, wherein the disease is systemic lupuserythematosus.
 23. The method of claim 11, wherein the disease ischronic obstructive pulmonary disorder.
 24. A method of treating orameliorating a syndrome, disorder or disease, in a subject in needthereof comprising administering to the subject an effective amount of acompound of claim 1 or composition or medicament thereof in acombination therapy with one or more anti-inflammatory agents, orimmunosuppressive agents, wherein said syndrome, disorder or disease isselected from the group consisting of: rheumatoid arthritis, andpsoriasis.